uu.seUppsala University Publications
Change search
Refine search result
12345 1 - 50 of 226
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the 'Create feeds' function.
  • 1.
    Ahl, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Liu, Haoyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Schreiber, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Roos, S.
    Swedish Univ Agr Sci, Uppsala BioCtr, Dept Microbiol, Uppsala, Sweden..
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lactobacillus reuteri increases mucus thickness and ameliorates dextran sulphate sodium-induced colitis in mice2016In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 217, no 4, p. 300-310Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of this study was to investigate whether two Lactobacillus reuteri strains (rat-derived R2LC and human-derived ATCC PTA 4659 (4659)) could protect mice against colitis, as well as delineate the mechanisms behind this protection.

    Methods: Mice were given L.reuteri R2LC or 4659 by gavage once daily for 14days, and colitis was induced by addition of 3% DSS (dextran sulphate sodium) to drinking water for the last 7days of this period. The severity of disease was assessed through clinical observations, histological evaluation and ELISA measurements of myeloperoxidase (MPO) and pro-inflammatory cytokines from colonic samples. Mucus thickness was measured invivo with micropipettes, and tight junction protein expression was assessed using immunohistochemistry.

    Results: Colitis severity was significantly reduced by L.reuteri R2LC or 4659 when evaluated both clinically and histologically. The inflammation markers MPO, IL-1, IL-6 and mKC (mouse keratinocyte chemoattractant) were increased by DSS and significantly reduced by the L.reuteri strains. The firmly adherent mucus thickness was reduced by DSS, but significantly increased by L.reuteri in both control and DSS-treated mice. Expression of the tight junction proteins occludin and ZO-1 was significantly increased in the bottom of the colonic crypts by L.reuteri R2LC.

    Conclusion: These results demonstrate that each of the two different L. reuteri strains, one human-derived and one-rat-derived, protects against colitis in mice. Mechanisms behind this protection could at least partly be explained by the increased mucus thickness as well as a tightened epithelium in the stem cell area of the crypts.

  • 2.
    Ahl, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Roos, Stefan
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    CX3CR1 deficiency alters response to L-reuteri treatment of DSS-induced colitis in mice2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 902.10Article in journal (Other academic)
  • 3.
    Almgren, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Wickerts, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Heinonen, Erkki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Högman, Marieann
    Side effects of endotracheal suction in pressure and volume controlled ventilation2004In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 125, no 3, p. 1077-1080Article in journal (Refereed)
    Abstract [en]

    STUDY OBJECTIVES:

    To investigate the effects of endotracheal suction in volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) with an open suction system (OSS) or a closed suction system (CSS).

    DESIGN:

    Randomized comparison.

    SETTING:

    Animal research laboratory.

    PATIENTS:

    Twelve healthy anesthetized pigs.

    INTERVENTIONS:

    The effects of endotracheal suction during VCV and PCV with tidal volume (VT) of 14 mL/kg were compared. A 60-mm inner-diameter endotracheal tube was used. Ten-second suction was performed using OSS and CSS with 12F and 14F catheters connected to - 14 kPa vacuum.

    MEASUREMENTS AND RESULTS:

    Thirty minutes after suction in PCV, VT was still decreased by 27% (p < 0.001), compliance (Crs) by 28% (p < 0.001), and PaO(2) by 26% (p < 0.001); PaCO(2) was increased by 42% (p < 0.0001) and venous admixture by 158% (p = 0.003). Suction in VCV affected only Crs (decreased by 23%, p < 0.001) and plateau pressure (increased by 24%, p < 0.001). The initial impairment of gas exchange following suction in VCV was no longer statistically significant after 30 min.

    CONCLUSIONS:

    In conclusion, endotracheal suction causes lung collapse leading to impaired gas exchange, an effect that is more severe and persistent in PCV than in VCV.

  • 4.
    Almgren, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Wickerts, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Högman, Marieann
    Post-suction recruitment manoeuvre restores lung function in healthy, anaesthetized pigs2004In: Anaesthesia and Intensive Care, ISSN 0310-057X, E-ISSN 1448-0271, Vol. 32, no 3, p. 339-345Article in journal (Refereed)
    Abstract [en]

    Endotracheal suction can cause partial lung collapse and hypoxia and alter lung mechanics. We investigated the effects of adding a recruitment manoeuvre directly after endotracheal suction to restore lung volume in volume-controlled ventilation and pressure-controlled ventilation modes. Five anaesthetized pigs were investigated. The effects of endotracheal suction with or without a recruitment manoeuvre were compared in random order. In volume-controlled ventilation, compliance decreased after suction from 33 +/- 5 to 26 +/- 6 ml x cmH2O(-1) (P<0.05), and 30 minutes later it remained decreased at 25 +/- 6 ml x cmH2O(-1). Venous admixture increased after suction from 5 +/- 2 to 8 +/- 4% (P<0.05), but had recovered at 30 minutes. In pressure-controlled ventilation, compliance decreased after suction from 34 +/- 3 to 25 +/- 7 ml x cmH2O(-1) (P<0.05), and 30 minutes later it remained decreased at 25 +/- 7 ml x cmH2O(-1). Venous admixture increased after suction from 5 +/- 2 to 13 +/- 7% (P<0.05), and had not recovered after 30 minutes, 10 +/- 4%. When a recruitment manoeuvre was applied directly after suction, no negative side-effects were registered in volume-controlled ventilation or pressure-controlled ventilation. We conclude that the impairment of lung mechanics and gas exchange induced by endotracheal suction can be prevented by a simple post-suction recruitment manoeuvre. Further studies are needed to identify a suitable suction recruitment manoeuvre in patients with diseased lungs.

  • 5.
    Atuma, C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Engstrand, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Helicobacter pylori extracts reduce gastric mucosal blood flow by a nitric oxide-independent but mast cell- and platelet-activating factor receptor-dependent pathway in rats1999In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 34, no 12, p. 1183-1189Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We have previously shown that water extracts from Helicobacter pylori reduce gastric mucosal blood flow by approximately 15%. It has also been suggested that H. pylori can inhibit endogenous nitric oxide (NO) biosynthesis. Our aim was to examine whether the reduction in blood flow induced by H. pylori is the direct consequence of an NO synthase inhibition and the possible involvement of mast cell degranulation.

    METHODS: A water extract was produced from wildtype strain 88-23. The extract was applied on the exteriorized gastric corporal mucosa in inactin-anesthetized rats, after removing as much as possible of the mucus layer, during intravital microscopy. Blood flow was measured with laser-Doppler flowmetry.

    RESULTS: In rats pretreated with the NO synthase inhibitor N-nitro-L-arginine there was a 19% +/- 6% reduction in blood flow 40 min after application of the extract, and a 27% +/- 9% reduction after another 20 min with saline. The reduction was abolished by concomitant pretreatment with the mast cell stabilizer ketotifen or the platelet-activating factor (PAF) receptor antagonist WEB2086.

    CONCLUSION: The reduction in mucosal blood flow induced by the extract was probably mediated through an acute inflammatory response involving mast cell degranulation with consequent PAF secretion. The effect on blood flow was not the result of a decrease in vascular tone due to an inhibition of endogenous NO biosynthesis.

  • 6.
    Becriovic Agic, Mediha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Jönsson, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Genetic association of oxidative stress and fluid accumulation makes Balb/CJ mice more sensitive to decompensated heart failure2017In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 963-964Article in journal (Other academic)
  • 7. Boekel, Jorrit
    et al.
    Källskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Rydén-Aulin, Monica
    Rhen, Mikael
    Richter-Dahlfors, Agneta
    Comparative tissue transcriptomics reveal prompt inter-organ communication in response to local bacterial kidney infection2011In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 12, p. 123-Article in journal (Refereed)
    Abstract [en]

    Background: Mucosal infections elicit inflammatory responses via regulated signaling pathways. Infection outcome depends strongly on early events occurring immediately when bacteria start interacting with cells in the mucosal membrane. Hitherto reported transcription profiles on host-pathogen interactions are strongly biased towards in vitro studies. To detail the local in vivo genetic response to infection, we here profiled host gene expression in a recent experimental model that assures high spatial and temporal control of uropathogenic Escherichia coli (UPEC) infection within the kidney of a live rat. Results: Transcriptional profiling of tissue biopsies from UPEC-infected kidney tissue revealed 59 differentially expressed genes 8 h post-infection. Their relevance for the infection process was supported by a Gene Ontology (GO) analysis. Early differential expression at 3 h and 5 h post-infection was of low statistical significance, which correlated to the low degree of infection. Comparative transcriptomics analysis of the 8 h data set and online available studies of early local infection and inflammation defined a core of 80 genes constituting a "General tissue response to early local bacterial infections". Among these, 25% were annotated as interferon-gamma (IFN-gamma) regulated. Subsequent experimental analyses confirmed a systemic increase of IFN-gamma in rats with an ongoing local kidney infection, correlating to splenic, rather than renal Ifng induction and suggested this inter-organ communication to be mediated by interleukin (IL)-23. The use of comparative transcriptomics allowed expansion of the statistical data handling, whereby relevant data could also be extracted from the 5 h data set. Out of the 31 differentially expressed core genes, some represented specific 5 h responses, illustrating the value of comparative transcriptomics when studying the dynamic nature of gene regulation in response to infections. Conclusion: Our hypothesis-free approach identified components of infection-associated multi-cellular tissue responses and demonstrated how a comparative analysis allows retrieval of relevant information from lower-quality data sets. The data further define marked representation of IFN-gamma responsive genes and a prompt inter-organ communication as a hallmark of an early local tissue response to infection.

  • 8.
    Broman, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Källskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    The influence of pethidine on renal hemodynamics, renal sympathetic nerve activity and catecholaminies during normothermia and hypothermia1997In: Nephrology (Carlton. Print), ISSN 1320-5358, E-ISSN 1440-1797, Vol. 3, no Suppl. 1, p. 345-345Article, book review (Other academic)
  • 9.
    Brown, Russell D.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Turner, Anita J.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Gibson, Karen J.
    Tubuloglomerular feedback response in the prenatal and postnatal ovine kidney2011In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 300, no 6, p. F1368-F1374Article in journal (Refereed)
    Abstract [en]

    Brown RD, Turner AJ, Carlstrom M, Persson AE, Gibson KJ. Tubuloglomerular feedback response in the prenatal and postnatal ovine kidney. Am J Physiol Renal Physiol 300: F1368-F1374, 2011. First published March 30, 2011; doi:10.1152/ajprenal. 00019.2011.-The tubuloglomerular feedback mechanism (TGF) plays an important role in regulating single-nephron glomerular filtration rate (GFR) by coupling distal tubular flow to arteriolar tone. It is not known whether TGF is active in the developing kidney or whether it can regulate renal vascular tone and thus GFR during intrauterine life. TGF characteristics were examined in late-gestation ovine fetuses and lambs under normovolemic and volume-expanded (VE) conditions. Lambs and pregnant ewes were anesthetized and the fetuses were delivered via a caesarean incision into a heated water bath, with the umbilical cord intact. Under normovolemic conditions, mean arterial pressure of the fetuses was lower than lambs (51 +/- 1 vs. 64 +/- 3 mmHg). The maximum TGF response (Delta P(SFmax)) was found to be lower in fetuses than lambs when tubular perfusion was increased from 0 to 40 nl/min (5.4 +/- 0.7 vs. 10.6 +/- 0.4 mmHg). Furthermore, the flow rate eliciting half-maximal response [turning point (TP)] was 15.7 +/- 0.9 nl/min in fetuses compared with 19.3 +/- 1.0 nl/min in lambs, indicating a greater TGF sensitivity of the prenatal kidney. VE decreased Delta P(SFmax) (4.2 +/- 0.4 mmHg) and increased TP to 23.7 +/- 1.3 nl/min in lambs. In fetuses, VE increased stop-flow pressure from 26.6 +/- 1.5 to 30.3 +/- 0.8 mmHg, and reset TGF sensitivity so that TP increased to 21.3 +/- 0.7 nl/min, but it had no effect on Delta P(SFmax). This study provides direct evidence that the TGF mechanism is active during fetal life and responds to physiological stimuli. Moreover, reductions in TGF sensitivity may contribute to the increase in GFR at birth.

  • 10.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Causal link between neonatal hydronephrosis and later development of hypertension2010In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 37, no 2, p. E14-E23Article in journal (Refereed)
    Abstract [en]

    1. Although congenital ureteral obstruction is a common disorder in infants, its pathophysiology remains poorly understood and its clinical management continues to be debated. During the past decade, the surgical management of non-symptomatic hydronephrosis in children has become more conservative, but the long-term physiological consequences of this new policy are unclear. 2. In experimental models with complete ureteral obstruction, tubular atrophy and interstitial inflammation occur rapidly. Although this type of obstruction is very rare in clinical practice, it is often referred to in clinical discussions. New studies, using a model with chronic partial ureteral obstruction, have demonstrated that hydronephrosis is associated with renal injuries and is causally related to hypertension. 3. The mechanisms underlying the development of hypertension in experimental hydronephrosis are complex and involve changes in both the renin-angiotensin system and renal sympathetic nerve activity. Furthermore, oxidative stress and nitric oxide deficiency in the diseased kidney, with consequent resetting of the tubuloglomerular feedback mechanism, appear to play a pivotal role in the development and maintenance of hypertension. 4. In view of the new knowledge regarding the long-term effects of partial ureteral obstruction, today's non-operative management of hydronephrosis should be reconsidered to prevent obstructive nephropathy and hypertension in later life.

  • 11.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Brown, Russell D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Zilmer, Mihkel
    Zabihi, Sheller
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Eriksson, Ulf J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Persson, A Erik G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    SOD1-Deficiency Causes Salt-Sensitivity and Aggravates Hypertension in Hydronephrosis2009In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 297, no 1, p. R82-R92Article in journal (Refereed)
    Abstract [en]

    Background: Hydronephrosis causes renal dysfunction and salt-sensitive hypertension, which is associated with NO-deficiency and abnormal tubuloglomerular feedback (TGF) response. We investigated the role of oxidative stress for salt-sensitivity and for hypertension in hydronephrosis. Methods: Hydronephrosis was induced in SOD1-transgenic (SOD1-tg), SOD1-deficient (SOD1-ko) and wild-type mice and in rats. In mice, telemetric measurements were performed during normal (0.7% NaCl) and high sodium (4% NaCl) diets and with chronic Tempol supplementation. 8-iso-prostaglandin-F2alpha (F2-IsoPs) and protein excretion profiles and histology were investigated. The acute effects of Tempol on blood pressure and TGF were studied in rats. Results: In hydronephrosis, wild-type mice developed salt-sensitive hypertension (114+/-1 to 120+/-2 mmHg) which was augmented in SOD1-ko (125+/-3 to 135+/-4 mmHg), but abolished in SOD1-tg (109+/-3 to 108+/-3 mmHg). SOD1-ko controls displayed salt-sensitive blood pressure (108+/-1 to 115+/-2 mmHg), which was not found in wild-types or SOD1-tg. Chronic Tempol treatment reduced blood pressure in SOD1-ko controls (-7 mmHg) and in hydronephrotic wild-types (-8 mmHg) and SOD1-ko mice (-16 mmHg), but had no effect on blood pressure in wild-type or SOD1-tg controls. SOD1-ko controls and hydronephrotic wild-type and SOD1-ko mice exhibited increased fluid excretion associated with increased F2-IsoPs and protein excretion. The renal histopathological changes found in hydronephrotic wild-types were augmented in SOD1-ko and diminished in SOD-tg mice. Tempol attenuated blood pressure and normalized TGF response in hydronephrosis (DeltaPSF: 15.2+/-1.2 to 9.1+/-0.6 mmHg, TP: 14.3+/-0.8 to 19.7+/-1.4 nl/min). Conclusion: Oxidative stress due to SOD1-deficiency causes salt-sensitivity and plays a pivotal role for the development of hypertension in hydronephrosis. Increased superoxide formation may enhance TGF response and thereby contribute to hypertension.

  • 12.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Lai, En Yin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Ma, Zufu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Patzak, Andreas
    Brown, Russell D.
    Department of Physiology, Monash University, Monash, Australia .
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Role of NOX2 in the regulation of afferent arteriole responsiveness2009In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 296, no 1, p. R72-R79Article in journal (Refereed)
    Abstract [en]

    NADPH oxidases (NOX) are the major source of reactive oxygen species (ROS) in the vasculature and contribute to the control of renal perfusion. The role of NOX2 in the regulation of blood pressure and afferent arteriole responsiveness was investigated in NOX2(-/-) and wild-type mice. Arteriole constrictions to ANG II (10(-14)-10(-6) mol/l) were weaker in NOX2(-/-) compared with wild types. N(omega)-nitro-l-arginine methyl ester (l-NAME; 10(-4) mol/l) treatment reduced basal diameters significantly more in NOX2(-/-) (-18%) than in wild types (-6%) and augmented ANG II responses. Adenosine (10(-11)-10(-4) mol/l) constricted arterioles of wild types but not of NOX2(-/-). However, simultaneous inhibition of adenosine type-2 receptors induced vasoconstriction, which was stronger in NOX2(-/-). Adenosine (10(-8) mol/l) enhanced the ANG II response in wild type, but not in NOX2(-/-). This sensitizing effect by adenosine was abolished by apocynin. Chronic ANG II pretreatment (14 days) did not change the ANG II responses in NOX2(-/-), but strengthened the response in wild types. ANG II pretreatment augmented the l-NAME response in NOX2(-/-) (-33%), but not in wild types. Simultaneous application of l-NAME and ANG II caused a stronger constriction in the NOX2(-/-) (-64%) than in wild types (-46%). Basal blood pressures were similar in both genotypes, however, chronic ANG II infusion elevated blood pressure to a greater extent in wild-type (15 +/- 1%) than in NOX2(-/-) (8 +/- 1%) mice. In conclusion, NOX2 plays an important role in the control of afferent arteriole tone and is involved in the contractile responses to ANG II and/or adenosine. NOX2 can be activated by elevated ANG II and may play an important role in ANG II-induced hypertension. NOX2-derived ROS scavenges nitric oxide, causing subsequent nitric oxide-deficiency.

  • 13.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Lai, En Yin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Steege, Andreas
    Sendeski, Mauricio
    Ma, Zufu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Zabihi, Sheller
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Eriksson, Ulf J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Patzak, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Nitric oxide deficiency and increased adenosine response of afferent arterioles in hydronephrotic mice with hypertension2008In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 51, no 5, p. 1386-1392Article, review/survey (Refereed)
    Abstract [en]

    Afferent arterioles were used to investigate the role of adenosine, angiotensin II, NO, and reactive oxygen species in the pathogenesis of increased tubuloglomerular feedback response in hydronephrosis. Hydronephrosis was induced in wild-type mice, superoxide dismutase-1 overexpressed mice (superoxide-dismutase-1 transgenic), and deficient mice (superoxide dismutase-1 knockout). Isotonic contractions in isolated perfused arterioles and mRNA expression of NO synthase isoforms, adenosine, and angiotensin II receptors were measured. In wild-type mice, N(G)-nitro-L-arginine methyl ester (L-NAME) did not change the basal arteriolar diameter of hydronephrotic kidneys (-6%) but reduced it in control (-12%) and contralateral arterioles (-43%). Angiotensin II mediated a weaker maximum contraction of hydronephrotic arterioles (-18%) than in control (-42%) and contralateral arterioles (-49%). The maximum adenosine-induced constriction was stronger in hydronephrotic (-19%) compared with control (-8%) and contralateral kidneys (+/-0%). The response to angiotensin II became stronger in the presence of adenosine in hydronephrotic kidneys and attenuated in contralateral arterioles. L-NAME increased angiotensin II responses of all of the groups but less in hydronephrotic kidneys. The mRNA expression of endothelial NO synthase and inducible NO synthase was upregulated in the hydronephrotic arterioles. No differences were found for adenosine or angiotensin II receptors. In superoxide dismutase-1 transgenic mice, strong but similar L-NAME response (-40%) was observed for all of the groups. This response was totally abolished in arterioles of hydronephrotic superoxide dismutase-1 knockout mice. In conclusion, hydronephrosis is associated with changes in the arteriolar reactivity of both hydronephrotic and contralateral kidneys. Increased oxidative stress, reduced NO availability, and stronger reactivity to adenosine of the hydronephrotic kidney may contribute to the enhanced tubuloglomerular feedback responsiveness in hydronephrosis and be involved in the development of hypertension.

  • 14.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Larsen, Filip J.
    Nystrom, Thomas
    Hezel, Michael
    Borniquel, Sara
    Weitzberg, Eddie
    Lundberg, Jon O.
    Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 41, p. 17716-17720Article in journal (Refereed)
    Abstract [en]

    The metabolic syndrome is a clustering of risk factors of metabolic origin that increase the risk for cardiovascular disease and type 2 diabetes. A proposed central event in metabolic syndrome is a decrease in the amount of bioavailable nitric oxide (NO) from endothelial NO synthase (eNOS). Recently, an alternative pathway for NO formation in mammals was described where inorganic nitrate, a supposedly inert NO oxidation product and unwanted dietary constituent, is serially reduced to nitrite and then NO and other bioactive nitrogen oxides. Here we show that several features of metabolic syndrome that develop in eNOS-deficient mice can be reversed by dietary supplementation with sodium nitrate, in amounts similar to those derived from eNOS under normal conditions. In humans, this dose corresponds to a rich intake of vegetables, the dominant dietary nitrate source. Nitrate administration increased tissue and plasma levels of bioactive nitrogen oxides. Moreover, chronic nitrate treatment reduced visceral fat accumulation and circulating levels of triglycerides and reversed the prediabetic phenotype in these animals. In rats, chronic nitrate treatment reduced blood pressure and this effect was also present during NOS inhibition. Our results show that dietary nitrate fuels a nitrate-nitrite-NO pathway that can partly compensate for disturbances in endogenous NO generation from eNOS. These findings may have implications for novel nutrition-based preventive and therapeutic strategies against cardiovascular disease and type 2 diabetes.

  • 15.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Important role of NAD(P)H oxidase 2 in the regulation of the tubuloglomerular feedback2009In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 53, no 3, p. 456-457Article in journal (Refereed)
  • 16.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, Anders Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hezel, Michael
    Scheffer, Peter G.
    Teerlink, Tom
    Weitzberg, Eddie
    Lundberg, Jon O.
    Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension2011In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 89, no 3, p. 574-585Article in journal (Refereed)
    Abstract [en]

    Aims Reduced bioavailability of endogenous nitric oxide (NO) is a central pathophysiological event in hypertension and other cardiovascular diseases. Recently, it was demonstrated that inorganic nitrate from dietary sources is converted in vivo to form nitrite, NO, and other bioactive nitrogen oxides. We tested the hypothesis that dietary inorganic nitrate supplementation may have therapeutic effects in a model of renal and cardiovascular disease.

    Methods and results Sprague-Dawley rats subjected to unilateral nephrectomy and chronic high-salt diet from 3 weeks of age developed hypertension, cardiac hypertrophy and fibrosis, proteinuria, and histological as well as biochemical signs of renal damage and oxidative stress. Simultaneous nitrate treatment (0.1 or 1 mmol nitrate kg(-1) day(-1)), with the lower dose resembling the nitrate content of a diet rich in vegetables, attenuated hypertension dose-dependently with no signs of tolerance. Nitrate treatment almost completely prevented proteinuria and histological signs of renal injury, and the cardiac hypertrophy and fibrosis were attenuated. Mechanistically, dietary nitrate restored the tissue levels of bioactive nitrogen oxides and reduced the levels of oxidative stress markers in plasma (malondialdehyde) and urine (Class VI F2-isoprostanes and 8-hydroxy-2-deoxyguanosine). In addition, the increased circulating and urinary levels of dimethylarginines (ADMA and SDMA) in the hypertensive rats were normalized by nitrate supplementation.

    Conclusion Dietary inorganic nitrate is strongly protective in this model of renal and cardiovascular disease. Future studies will reveal if nitrate contributes to the well-known cardioprotective effects of a diet rich in vegetables.

  • 17.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Wåhlin, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Skott, Ole
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Relief of chronic partial ureteral obstruction attenuates salt-sensitive hypertension in rats2007In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 189, no 1, p. 67-75Article in journal (Refereed)
    Abstract [en]

    Aim: The incidence of hydronephrosis due to ureteropelvic junction obstruction is approx. 0.5%. During the last decade, the management of non-symptomatic hydronephrosis has become much more conservative, but the long-term physiological consequences of this policy are not clear. Previously, we have shown that animals with chronic partial unilateral ureteral obstruction develop salt-sensitive hypertension. In this study, the effects of ipsilateral and contralateral nephrectomy and ureterovesicostomy on blood pressure were studied in hydronephrotic animals.

    Methods: Partial unilateral ureteral obstruction was created in 3-week-old male Sprague–Dawley rats and blood pressure was measured telemetrically 4–6 weeks later during a normal and high salt diet before and after uninephrectomy or ureterovesicostomy. Plasma samples for renin assay were collected during both diets before and after ipsilateral nephrectomy.

    Results: All hydronephrotic animals developed salt-sensitive hypertension, of different degrees. Before nephrectomy the plasma renin concentration was significantly higher in the hydronephrotic animals than in controls (160 ± 15 μGU mL−1 vs. 96 ± 12 μGU mL−1, respectively), but after the ipsilateral nephrectomy no differences were found between the groups. In the hydronephrotic animals both ipsilateral nephrectomy and ureterovesicostomy reduced the blood pressure and salt-sensitivity but the former still differed significantly from the controls. In contralaterally, nephrectomized hydronephrotic animals the salt-sensitive hypertension became more pronounced.

    Conclusion: Hydronephrosis in rats causes salt-sensitive hypertension that can be markedly reduced by removing the hydronephrotic kidney or relieving the obstruction by ureterovesicostomy. The mechanisms appear to be intrarenal and primarily located in the diseased kidney, but a secondary mechanism is also present.

  • 18.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Wåhlin, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Skott, Ole
    Brown, Russell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Hydronephrosis causes salt-sensitive hypertension in rats2006In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 24, no 7, p. 1437-1443Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hypertension is a common disease in the Western world and approximately 5% of all cases are secondary to kidney malfunction. It is not clear whether unilateral hydronephrosis due to partial obstruction affects blood pressure. AIM: The aim of this study was to determine whether hypertension develops and to investigate the effects of different salt diets on the blood pressure in hydronephrotic animals. METHODS: Unilateral partial ureteral obstruction was created in 3-week-old Sprague-Dawley rats. A telemetric device was implanted 4-6 weeks later and blood pressure was measured on normal, low- and high-salt diets. Plasma samples were collected on all diets for renin analysis. RESULTS: All hydronephrotic animals developed hypertension that correlated to the degree of hydronephrosis. The blood pressure increased slowly with time and was salt sensitive. In severe hydronephrosis, blood pressure increased from 118 ± 5 mmHg on low salt to 140 ± 6 mmHg on high salt intake, compared to control levels of 82 ± 2 and 84 ± 2 mmHg, respectively. Plasma renin concentration was increased in the hydronephrotic group of animals compared to controls on all diets, but the difference was only significant on a normal salt diet, 165 ± 15 versus 86 ± 12 μGU/ml respectively. In animals with severe hydronephrosis the plasma renin levels were lower, and the changes less, than in those with mild and moderate hydronephrosis. CONCLUSION: This study demonstrates the presence of a salt-sensitive hypertension in hydronephrosis. A systemic effect of the renin-angiotensin system alone cannot be responsible for the hypertension.

  • 19.
    Christensen, Michael
    et al.
    Aarhus Univ, Aarhus N, Denmark..
    Schiffer, Tomas A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Norregaard, Rikke
    Aarhus Univ, Aarhus N, Denmark..
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Metformin Normalises Medullary Hypoxia in The Diabetic Rat Kidney2017In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31Article in journal (Other academic)
  • 20.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Leukocytes in Angiogenesis: Learning from Transplanted Pancreatic Islets2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Angiogenesis, the growth of new blood vessels, is a complex process involving several cell types and molecular signals. Excessive vascular growth is a problem in tumors, and insufficient vascularization hampers the function of transplanted insulin-producing pancreatic islets. Understanding the mechanisms behind blood vessel growth generates increased means to control angiogenesis. In this thesis a model of pancreatic islet transplantation to muscle has been used to study the involvement of leukocytes in the development of new vasculature.

    Transplantation of isolated islets of Langerhans into mouse muscle promoted revascularization of the grafts to a level comparable to native islets in the pancreas. The complete and functional vascular restoration resulted in improved blood glucose control compared to the clinical standard implantation site, the liver. This proved muscle as a transplantation site to be a clinically relevant option for the treatment of type 1 diabetes.

    The rapid islet revascularization process was found to be dependent on a distinct subset of neutrophils characterized by high expression of the chemokine receptor CXCR4 and the enzyme matrix metalloproteinase 9 (MMP-9). These cells were recruited to recently transplanted and hypoxic grafts by islet-secreted vascular endothelial growth factor A (VEGF-A). Leukocyte migration and interactions in the engraftment area were monitored using a high-speed confocal microscope followed by software tracking. New software was developed to visualize migration statistics. This tool revealed areas around the islet graft where neutrophil gathering coincided with sites of angiogenesis. Macrophages in the engraftment area positioned themselves close to the newly formed vasculature and were shown to have a stabilizing effect on the vessels. When macrophages were removed, no pericytes were recruited to the forming vasculature. The perivascular macrophages also began to express a pericyte marker when in the graft, suggesting a close relationship between these cell types or macrophage plasticity.

    In conclusion, this thesis presents muscle as a proangiogenic transplantation site for pancreatic islets for the treatment of type 1 diabetes, where the revascularization of the grafts was dependent on the recruitment and actions of specialized immune cells.

    List of papers
    1. Clinical and Experimental Pancreatic Islet Transplantation to Striated Muscle: Establishment of a Vascular System Similar to that in Native Islets
    Open this publication in new window or tab >>Clinical and Experimental Pancreatic Islet Transplantation to Striated Muscle: Establishment of a Vascular System Similar to that in Native Islets
    Show others...
    2010 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, no 10, p. 2569-2578Article in journal (Refereed) Published
    Abstract [en]

    Objective: Curing type 1 diabetes by transplanting pancreatic islets into the liver is associated with poor long-term outcome and graft failure at least partly due to inadequate graft revascularization. The aim of the current study was to evaluate striated muscle as a potential angiogenic site for islet transplantation. Research Design and Methods: The current study presents a new experimental model which is found applicable to clinical islet transplantation. Islets were implanted into striated muscle where after intra-islet vascular density and blood flow were visualized with intravital and confocal microscopy in mice, and by magnetic resonance imaging in three auto-transplanted pancreatectomized patients. Mice were rendered neutropenic by repeated injections of Gr-1 antibody and diabetes was induced by alloxan treatment. Results: Contrary to liver-engrafted islets, islets transplanted to mouse muscle were revascularized with vessel densities and blood flow entirely comparable to islets within intact pancreas. Initiation of islet revascularization at the muscular site was dependent on neutrophils, and the function of islets transplanted to muscle was proven by curing diabetic mice. The experimental data were confirmed in auto-transplanted patients where higher plasma volumes were measured in islets engrafted in forearm muscle compared to adjacent muscle tissue through high-resolution magnetic resonance imaging. Conclusions: This study presents a novel paradigm in islet transplantation whereby recruited neutrophils are crucial for the functionally restored intra-islet blood perfusion following transplantation to striated muscle under experimental and clinical situations.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-130874 (URN)10.2337/db10-0205 (DOI)000283205700030 ()20651296 (PubMedID)
    Funder
    Swedish Research Council, 57p-20680, 57x-20675
    Available from: 2010-09-15 Created: 2010-09-15 Last updated: 2017-12-12Bibliographically approved
    2. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue
    Open this publication in new window or tab >>VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue
    Show others...
    2012 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 23, p. 4653-4662Article in journal (Refereed) Published
    Abstract [sv]

    Recruitment and retention of leukocytes at a site of blood vessel growth are crucial for proper angiogenesis and subsequent tissue perfusion. Although critical for many aspects of regenerative medicine, the mechanisms of leukocyte recruitment to and actions at sites of angiogenesis are not fully understood. In this study, we investigated the signals attracting leukocytes to avascular transplanted pancreatic islets and leukocyte actions at the engraftment site. Expression of the angiogenic stimulus VEGF-A by mouse pancreatic islets was elevated shortly after syngeneic transplantation to muscle. High levels of leukocytes, predominantly CD11b+/Gr-1+/CXCR4hi neutrophils, were observed at the site of engraftment, whereas VEGF-A–deficient islets recruited only half of the amount of leukocytes when transplanted. Acute VEGF-A exposure of muscle increased leukocyte extravasation but not the levels of SDF-1α. VEGF-A–recruited neutrophils expressed 10 times higher amounts of MMP-9 than neutrophils recruited to an inflammatory stimulus. Revascularization of islets transplanted to MMP-9–deficient mice was impaired because blood vessels initially failed to penetrate grafts, and after 2 weeks vascularity was still disturbed. This study demonstrates that VEGF-A recruits a proangiogenic circulating subset of CD11b+/Gr-1+ neutrophils that are CXCR4hi and deliver large amounts of the effector protein MMP-9, required for islet revascularization and functional integration after transplantation.

    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-188352 (URN)10.1182/blood-2012-04-421040 (DOI)000313113300031 ()
    Available from: 2012-12-16 Created: 2012-12-16 Last updated: 2018-01-11Bibliographically approved
    3. Vascular sprouts induce local attraction of proangiogenic neutrophils
    Open this publication in new window or tab >>Vascular sprouts induce local attraction of proangiogenic neutrophils
    Show others...
    2017 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 102, p. 741-751Article in journal (Refereed) Published
    National Category
    Physiology Bioinformatics (Computational Biology)
    Identifiers
    urn:nbn:se:uu:diva-196483 (URN)10.1189/jlb.1MA0117-018R (DOI)000413395700019 ()
    Projects
    eSSENCE
    Available from: 2017-06-05 Created: 2013-03-10 Last updated: 2018-02-07Bibliographically approved
    4. Pericyte repopulation of transplanted pancreatic islets is macrophage dependent
    Open this publication in new window or tab >>Pericyte repopulation of transplanted pancreatic islets is macrophage dependent
    (English)Manuscript (preprint) (Other academic)
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-196485 (URN)
    Available from: 2013-03-10 Created: 2013-03-10 Last updated: 2018-01-11
  • 21.
    Christoffersson, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Intramuscular islet transplantation promotes restored islet vascularity2011In: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 3, no 2, p. 69-71Article in journal (Other academic)
    Abstract [en]

    In a recent publication, we reported that islets transplanted to mouse striated muscle became revascularized with intra-islet vessel densities comparable to native islets. Revascularization of islet grafts was completely dependent on recruited Gr-1+ leukocytes. Diabetic mice cured by transplantation of 300 islets into muscle handled glucose tolerance tests as healthy controls, whereas mice cured by intraportal islet transplantation into the liver had increased blood glucose values during the load. The translational impact of these observations were confirmed by magnetic resonance imaging of autotransplanted islets in the forearm muscle of pancreactomized patients, and higher blood perfusion of the grafts compared to adjacent muscle were found. In summary, the striated muscle is a promising site for islet transplantation which promotes full revascularization of implanted grafts. The proangiogenic role of recruited leukocytes during engraftment needs to be further characterized, and considered for immune suppression treatments.

  • 22.
    Christoffersson, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Olsen, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Pericyte repopulation of transplanted pancreatic islets is macrophage dependentManuscript (preprint) (Other academic)
  • 23.
    Christoffersson, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Vandooren, Jennifer
    Liden, Majken
    Massena, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Reinert, RB
    Brissova, M
    Powers, AC
    Opdenakker, Ghislain
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue2012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 23, p. 4653-4662Article in journal (Refereed)
    Abstract [sv]

    Recruitment and retention of leukocytes at a site of blood vessel growth are crucial for proper angiogenesis and subsequent tissue perfusion. Although critical for many aspects of regenerative medicine, the mechanisms of leukocyte recruitment to and actions at sites of angiogenesis are not fully understood. In this study, we investigated the signals attracting leukocytes to avascular transplanted pancreatic islets and leukocyte actions at the engraftment site. Expression of the angiogenic stimulus VEGF-A by mouse pancreatic islets was elevated shortly after syngeneic transplantation to muscle. High levels of leukocytes, predominantly CD11b+/Gr-1+/CXCR4hi neutrophils, were observed at the site of engraftment, whereas VEGF-A–deficient islets recruited only half of the amount of leukocytes when transplanted. Acute VEGF-A exposure of muscle increased leukocyte extravasation but not the levels of SDF-1α. VEGF-A–recruited neutrophils expressed 10 times higher amounts of MMP-9 than neutrophils recruited to an inflammatory stimulus. Revascularization of islets transplanted to MMP-9–deficient mice was impaired because blood vessels initially failed to penetrate grafts, and after 2 weeks vascularity was still disturbed. This study demonstrates that VEGF-A recruits a proangiogenic circulating subset of CD11b+/Gr-1+ neutrophils that are CXCR4hi and deliver large amounts of the effector protein MMP-9, required for islet revascularization and functional integration after transplantation.

  • 24.
    Christoffersson, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Waldén, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Opdenakker, Ghislain
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Matrix Metalloproteinase-9 Is Essential for Physiological Beta Cell Function and Islet Vascularization in Adult Mice2015In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 185, no 4, p. 1094-1103Article in journal (Refereed)
    Abstract [en]

    The availability of paracrine factors in the islets of Langerhans, and the constitution of the beta cell basement membrane can both be affected by proteolytic enzymes. This study aimed to investigate the effects of the extraceaular matrix-degrading enzyme gelatinase B/matrix metalloproteinase-9 (Mmp-9) on islet function in mice. Islet function of Mmp9-deficient (Mmp9(-/-)) mice and their wild-type Littermates was evaluated both in vivo and in vitro. The pancreata of Mmp9(-/-) mice did not differ from wild type in islet mass or distribution. However, Mmp9(-/-) mice had an impaired response to a glucose toad in vivo, with lower serum insulin levels. The glucose-stimulated insulin secretion was reduced also in vitro in isolated Mmp9(-/-) islets. The vascular density of Mmp9(-/-) islets was lower, and the capillaries had fewer fenestrations, whereas the islet blood flow was threefold higher. These alterations could partly be explained by compensatory changes in the expression of matrix-related proteins. This in-depth investigation of the effects of the loss of MMP9(-/-) function on pancreatic islets uncovers a deteriorated beta cell function that is primarily due to a shift in the beta cell phenotype, but also due to islet vascular aberrations. This likely reflects the importance of a normal islet matrix turnover exerted by MMP-9, and concomitant release of paracrine factors sequestered on the matrix.

  • 25.
    Christoffersson, Gustav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Zang, Guangxiang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Zhuang, Zhen W.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Simons, Michael
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vascular adaptation to a dysfunctional endothelium as a consequence of Shb deficiency2012In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 15, no 3, p. 469-480Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF)-A regulates angiogenesis, vascular morphology and permeability by signaling through its receptor VEGFR-2. The Shb adapter protein has previously been found to relay certain VEGFR-2 dependent signals and consequently vascular physiology and structure was assessed in Shb knockout mice. X-ray computed tomography of vessels larger than 24 mm diameter (micro-CT) after contrast injection revealed an increased frequency of 48-96 µm arterioles in the hindlimb calf muscle in Shb knockout mice. Intravital microscopy of the cremaster muscle demonstrated a less regular vasculature with fewer branch points and increased vessel tortuosity, changes that led to an increased blood flow velocity. Reduced in vivo angiogenesis was observed in Shb knockout MatrigelTM plugs. Unlike the wild-type situation, VEGF-A did not provoke a dissociation of VE-cadherin from adherens junctions in Shb knockout venules. The reduced angiogenesis and altered properties of junctions had consequences for two patho-physiological responses to arterial occlusion: vascular permeability was reduced in the Shb knockout cremaster muscle after ligation of one supplying artery and heat-induced blood flow determined by Laser-Doppler measurements was decreased in the hindlimb after ligation of the femoral artery. Consequently, the Shb knockout mouse exhibited structural and functional (angiogenesis and vascular permeability) vascular abnormalities that have implications for understanding the function of VEGF-A under physiological conditions.

  • 26. Davids, Mariska
    et al.
    Swieringa, Eliane
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Smith, Desiree E. C.
    Smulders, Yvo M.
    Scheffer, Peter G.
    Blom, Henk J.
    Teerlink, Tom
    Simultaneous determination of asymmetric and symmetric dimethylarginine, L-monomethylarginine, L-arginine, and L-homoarginine in biological samples using stable isotope dilution liquid chromatography tandem mass spectrometry2012In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 900, p. 38-47Article in journal (Refereed)
    Abstract [en]

    Production of the endogenous vasodilator nitric oxide (NO) from L-arginine by NO synthase is modulated by L-homoarginine, L-monomethylargine (MMA), asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Here we report on a stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of these metabolites in plasma, cells and tissues. After addition of the internal standards (D-7-ADMA, D-4-L-homoarginine and C-13(6)-Larginine), analytes were extracted from the samples using Waters Oasis MCX solid phase extraction cartridges. Butylated analytes were separated isocratically on a Waters XTerra MS C18 column (3.5 mu m. 3.9 mm x 100 mm) using 600 mg/L ammonium formate in water - acetonitrile (95.5:4.5, v/v) containing 0.1 vol% formic acid, and subsequently measured on an AB Sciex API 3000 triple quadrupole mass spectrometer. Multiple reaction monitoring in positive mode was used for analyte quantification. Validation was performed in plasma. Calibration lines were linear (r(2) >= 0.9979) and lower limits of quantification in plasma were 0.4 nM for ADMA and SDMA and 0.8 nM for the other analytes. Accuracy (% bias) was <3% except for MMA (<7%), intra-assay precision (expressed as CV) was <3.5%, inter-assay precision <9.6%, and recovery 92.9-103.2% for all analytes. The method showed good correlation (r(2) >= 0.9125) with our previously validated HPLC-fluorescence method for measurement in plasma, and was implemented with good performance for measurement of tissue samples. Application of the method revealed the remarkably fast (i.e. within 60 min) appearance in plasma of stable isotope-labeled ADMA, SDMA, and MMA during infusion of D-3-methyl-1-C-13-methionine in healthy volunteers.

  • 27.
    Do, Lan
    et al.
    Umeå universitet.
    Dahl, Christen P
    Kerje, Susanne
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Mörner, Stellan
    Lindqvist, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Engström-Laurent, Anna
    Larsson, Göran
    Hellman, Urban
    High Sensitivity Method to Estimate Distribution of Hyaluronan Molecular Sizes in Small Biological Samples Using Gas-Phase Electrophoretic Mobility Molecular Analysis2015In: International Journal of Cell Biology, ISSN 1687-8876, E-ISSN 1687-8884, Vol. 2015, article id 938013Article in journal (Refereed)
    Abstract [en]

    Hyaluronan is a negatively charged polydisperse polysaccharide where both its size and tissue concentration play an important role in many physiological and pathological processes. The various functions of hyaluronan depend on its molecular size. Up to now, it has been difficult to study the role of hyaluronan in diseases with pathological changes in the extracellular matrix where availability is low or tissue samples are small. Difficulty to obtain large enough biopsies from human diseased tissue or tissue from animal models has also restricted the study of hyaluronan. In this paper, we demonstrate that gas-phase electrophoretic molecular mobility analyzer (GEMMA) can be used to estimate the distribution of hyaluronan molecular sizes in biological samples with a limited amount of hyaluronan. The low detection level of the GEMMA method allows for estimation of hyaluronan molecular sizes from different parts of small organs. Hence, the GEMMA method opens opportunity to attain a profile over the distribution of hyaluronan molecular sizes and estimate changes caused by disease or experimental conditions that has not been possible to obtain before.

  • 28.
    Eckerbom, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Bjerner, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Intravoxel Incoherent Motion MR Imaging of the Kidney: Pilot Study2013In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, p. 55-58Article in journal (Refereed)
    Abstract [en]

    MR examinations (Achieva 3 T, Philips, Best, The Netherlands) were performed at five different occasions in a healthy volunteer (male 60 years) and in one renal cancer patient (male 78 years) with normal renal function (creatinine 88 μmol/L). Intravoxel incoherent motion (IVIM) coefficients D + D* were measured using respiratory-triggered diffusion-weighted spin-echo echo-planar imaging. Perfusion data of the patient were acquired using a saturation-recovery gradient-echo sequence and with the bolus of Gd-BOPTA (Multihance). D + D* were computed by monoexponential fitting of MR signal intensity attenuation versus b for b = 0, 50, 100, 150 s/mm2. Perfusion parameters were evaluated with “NordicICE” software. The map of D + D* was compared qualitatively with the perfusion map computed from the Gd scan. D + D* values of the cortex and medulla were in the range 2.3–2.7 and 1.1–1.6 × 10-3 mm2/s, respectively. In conclusion, in this pilot study a good qualitative relation between IVIM variables D + D* and renal perfusion has been found.

  • 29.
    Edlund, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    The roles of NADPH-oxidase and nNOS for the increased oxidative stress and the oxygen consumption in the diabetic kidney2010In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 26, no 5, p. 349-356Article in journal (Refereed)
    Abstract [en]

    Background

    Sustained hyperglycaemia induces increased renal oxygen consumption resulting in reduced oxygen availability in the diabetic kidney. We investigated the roles of the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase and the neuronal nitric oxide synthase (nNOS) for the increased oxygen consumption in streptozotocin-diabetic rats.

    Methods

    Oxygen consumption was measured in isolated proximal tubular cells (PTC) from streptozotocin-induced diabetic rats (n = 7-9 per group) with and without chronic treatment with apocynin, a NADPH-oxidase inhibitor, or S-methyl-L-thiocitrulline (SMTC), a selective nNOS inhibitor, or a combination of the two and the results were compared to normoglycaemic controls (n = 10). Oxidative stress was estimated from thiobarbituric acid reactive substances and protein expression measured by Western blot.

    Results

    Proximal tubular cells from untreated diabetic rats had increased oxygen consumption compared to controls (40.6 +/- 7.9 versus 10.9 +/- 2.0 nmol/mg protein/min). All treatments reduced the diabetes-induced increase in oxygen consumption (apocynin 10.5 +/- 1.7, SMTC 19.7 +/- 3.0 and apocynin +/- SMTC 21.6 +/- 3.6 nmol/mg protein/min). Neither apocynin nor SMTC had any effect on the oxygen consumption in cells pre-incubated with ouabain, an inhibitor of active electrolyte transport. Oxidative stress was elevated in the diabetic kidney and inhibited by all treatments. The increased oxygen consumption by diabetic proximal tubular cells correlated with increased protein expressions of p47phox and nNOS and the treatments prevented these increases.

    Conclusions

    Diabetes induces oxidative stress, which increases oxygen consumption in proximal tubular cells. Inhibition of either NADPH-oxidase or nNOS prevented the increased oxygen consumption. The effect of blocking both these enzymes was less than additive suggesting overlapping pathways which warrant further studies.

  • 30.
    Edlund, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Glickson, Jerry D.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Reduced oxygenation in diabetic rat kidneys measured by T2* weighted magnetic resonance micro-imaging2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, p. 199-204Article in journal (Refereed)
    Abstract [en]

    By applying invasive techniques for direct measurements of oxygen tension, we have reported decreased kidney oxygenation in experimental diabetes in rats. However, the non-invasive MRI technique utilizing the BOLD effect provides several advantages with the possibility to perform repetitive measurements in the same animals and in human subjects. In this study, we applied a modified single gradient echo micro-imaging sequence to detect the BOLD effect in kidneys of diabetic rats and compared the results to normoglycemic controls. All measurements were performed on inactin-anaesthetized adult male Wistar Furth rats. Diabetes was induced by streptozotocin (45 mg/kg) 14 days prior to MRI-analysis. Sixteen T2*-weighted image records (B0=1.5 T) were performed using radiofrequency spoiled gradient echo sequence with 2.6 ms step increments of TE (TE1=12 ms), while TR (75 ms) and bandwidth per pixel (71.4 Hz) were kept constant. T2* maps were computed by mono-exponential fitting of the pixel intensities. Relaxation rates R2* (1/T2*) in cortex and outer stripe of the outer medulla were similar in both groups (cortex for controls 22.3 +/- 0.4 vs. diabetics 23.1 +/- 1.8 Hz and outer stripe of outer medulla for controls 24.9 +/- 0.4 vs. diabetics 26.4 +/- 1.8 Hz; n=4 in both groups), whereas R2* was increased in the inner stripe of the outer medulla in diabetic rats (diabetics 26.1 +/- 2.4 vs. controls 18.8 +/- 1.4 Hz; n=4, P<0.05). This study demonstrates that experimental diabetes in rats induces decreased oxygenation of the renal outer medulla. Furthermore, the proposed T2*-weighted MR micro-imaging technique is suitable for detection of regional changes in kidney oxygenation in experimental animal models.

  • 31.
    Franzen, Stephanie
    et al.
    Linkoping Univ, Expt Renal Med, Div Drug Res, Dept Med & Hlth Sci,Fac Hlth Sci, S-58185 Linkoping, Sweden.;Linkoping Univ, Ctr Med Image Sci & Visualizat, S-58185 Linkoping, Sweden..
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Linkoping Univ, Expt Renal Med, Div Drug Res, Dept Med & Hlth Sci,Fac Hlth Sci, S-58185 Linkoping, Sweden.;Linkoping Univ, Ctr Med Image Sci & Visualizat, S-58185 Linkoping, Sweden..
    Endothelin type A receptor inhibition normalises intrarenal hypoxia in rats used as a model of type 1 diabetes by improving oxygen delivery2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 10, p. 2435-2442Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Intrarenal tissue hypoxia, secondary to increased oxygen consumption, has been suggested as a unifying mechanism for the development of diabetic nephropathy. Increased endothelin-1 signalling via the endothelin type A receptor (ETA-R) has been shown to contribute to the development of chronic kidney disease, but its role in kidney oxygen homeostasis is presently unknown. Methods The effects of acute ETA-R inhibition (8 nmol/l BQ-123 for 30-40 min directly into the left renal artery) on kidney function and oxygen metabolism were investigated in normoglycaemic control and insulinopenic male Sprague Dawley rats (55 mg/kg streptozotocin intravenously 2 weeks before the main experiment) used as a model of type 1 diabetes. Results Local inhibition of ETA-R in the left kidney did not affect BP in either the control or the diabetic rats. As previously reported, diabetic rats displayed increased kidney oxygen consumption resulting in tissue hypoxia in both the kidney cortex and medulla. The inhibition of ETA-Rs restored normal kidney tissue oxygen availability in the diabetic kidney by increasing renal blood flow, but did not affect oxygen consumption. Furthermore, ETA-R inhibition reduced the diabetes-induced glomerular hyperfiltration and increased the urinary sodium excretion. Kidney function in normoglycaemic control rats was largely unaffected by BQ-123 treatment, although it also increased renal blood flow and urinary sodium excretion in these animals. Conclusions/interpretation Acutely reduced intrarenal ETA-R signalling results in significantly improved oxygen availability in the diabetic kidney secondary to elevated renal perfusion. Thus, the beneficial effects of ETA-R inhibition on kidney function in diabetes may be due to improved intrarenal oxygen homeostasis.

  • 32.
    Franzen, Stephanie
    et al.
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.;Linkoping Univ, Ctr Med Image Sci & Visualizat, Linkoping, Sweden..
    Pihl, Liselotte
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Khan, Nadeem
    Geisel Sch Med Dartmouth, EPR Ctr Study Viable Syst, Dept Radiol, Hanover, NH USA..
    Gustafsson, Håkan
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.;Linkoping Univ, Ctr Med Image Sci & Visualizat, Linkoping, Sweden.;Linkoping Univ, Dept Radiol Norrkoping, Linkoping, Sweden..
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.;Linkoping Univ, Ctr Med Image Sci & Visualizat, Linkoping, Sweden..
    Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice2016In: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, ISSN 1931-857X, Vol. 310, no 9, p. F807-F809Article in journal (Refereed)
    Abstract [en]

    Intrarenal tissue hypoxia has been proposed as a unifying mechanism for the development of chronic kidney disease, including diabetic nephropathy. However, hypoxia has to be present before the onset of kidney disease to be the causal mechanism. To establish whether hypoxia precedes the onset of diabetic nephropathy, we implemented a minimally invasive electron paramagnetic resonance oximetry technique using implanted oxygen sensing probes for repetitive measurements of in vivo kidney tissue oxygen tensions in mice. Kidney cortex oxygen tensions were measured before and up to 15 days after the induction of insulinopenic diabetes in male mice and compared with normoglycemic controls. On day 16, urinary albumin excretions and conscious glomerular filtration rates were determined to define the temporal relationship between intrarenal hypoxia and disease development. Diabetic mice developed pronounced intrarenal hypoxia 3 days after the induction of diabetes, which persisted throughout the study period. On day 16, diabetic mice had glomerular hyperfiltration, but normal urinary albumin excretion. In conclusion, intrarenal tissue hypoxia in diabetes precedes albuminuria thereby being a plausible cause for the onset and progression of diabetic nephropathy.

  • 33. Franzen, Stephanie
    et al.
    Pihl, Liselotte
    Khan, Nadeem
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Gustafsson, Hakan
    Repetitive Measurements of Intrarenal Oxygenation In Vivo Using L Band Electron Paramagnetic Resonance2014In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 812, p. 135-141Article in journal (Refereed)
    Abstract [en]

    Intrarenal oxygenation is heterogeneous with oxygen levels normally being highest in the superficial cortex and lowest in the inner medulla. Reduced intrarenal oxygenation has been implied in the pathology of several kidney diseases. However, there is currently no method available to repetitively monitor regional renal oxygenation using minimally invasive procedures. We therefore evaluated implantable lithium phthalocyanine (LiPc) probes, which display a close correlation between EPR line width and oxygen availability. LiPc probes were implanted in the kidney cortex and medulla in the same mouse and sEPR spectra were acquired using a L band scanner during inhalation of air (21 % oxygen) or a mixture of air and nitrogen (10 % oxygen). In order to separate the signals from the two probes, a 1 G/cm gradient was applied and the signals were derived from 40 consecutive sweeps. Peak-to-peak comparison of the EPR line was used to convert the signal to an approximate oxygen tension in MATLAB. Kidney cortex as well as medullary oxygenation was stable over the 45 day period (cortex 56 +/- 7 mmHg and medulla 43 +/- 6 mmHg). However, 10 % oxygen inhalation significantly reduced oxygenation in both cortex (56 +/- 6 to 34 +/- 2 mmHg n = 15 p < 0.05) and medulla (42 +/- 5 to 29 +/- 3 mmHg n = 7 p < 0.05). In conclusion, L band EPR using LiPc probes implanted in discrete intrarenal structures can be used to repetitively monitor regional renal oxygenation. This minimally invasive method is especially well suited for conditions of reduced intrarenal oxygenation since this increases the signal intensity which facilitates the quantification of the EPR signal to absolute oxygenation values.

  • 34.
    Friederich, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells2008In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1777, no 7-8, p. 935-940Article in journal (Refereed)
    Abstract [en]

    We have previously reported increased O(2) consumption unrelated to active transport by tubular cells and up-regulated mitochondrial uncoupling protein (UCP)-2 expressions in diabetic kidneys. It is presently unknown if the increased UCP-2 levels in the diabetic kidney results in mitochondrial uncoupling and increased O(2) consumption, which we therefore investigated in this study. The presence of UCP-2 in proximal tubular cells was confirmed by immunohistochemistry and found to be increased (western blot) in homogenized tissue and isolated mitochondria from kidney cortex of diabetic rats. Isolated proximal tubular cells had increased total and ouabain-insensitive O(2) consumption compared to controls. Isolated mitochondria from diabetic animals displayed increased glutamate-stimulated O(2) consumption (in the absence of ADP and during inhibition of the ATP-synthase by oligomycin) compared to controls. Guanosine diphosphate, an UCP inhibitor, and bovine serum albumin which removes fatty acids that are essential for UCP-2 uncoupling activity, independently prevented the increased glutamate-stimulated O(2) consumption in mitochondria from diabetic animals. In conclusion, diabetic rats have increased mitochondrial UCP-2 expression in renal proximal tubular cells, which results in mitochondrial uncoupling and increased O(2) consumption. This mechanism may be protective against diabetes-induced oxidative stress, but will increase O(2) usage. The subsequently reduced O(2) availability may contribute to diabetes-induced progressive kidney damage.

  • 35.
    Friederich, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Diabetes, oxidative stress, nitric oxide and mitochondria function2009In: Current diabetes reviews, ISSN 1875-6417, Vol. 5, no 2, p. 120-144Article in journal (Refereed)
    Abstract [en]

    The role of altered mitochondria function has recently emerged as an important mechanism for the development of diabetic complications. Altered mitochondria function has also been implicated in the ageing process, defective insulin secretion, hypertension, arteriosclerosis, ischemia-reperfusion injury and apoptosis. Normally, the mitochondria are associated with ATP production using primarily pyruvate as the substrate, but recent reports indicate that tissue specific preferences exist. Also, the mitochondria are a substantial source of superoxide production, preferentially during states of elevated intracellular glucose concentrations. The mitochondria function is regulated by several factors including nitric oxide, oxidative stress, mammalian target of rapamycin, ADP and P(i) availability, which result in a complex regulation of ATP production and oxygen consumption, but also superoxide generation. These factors seem to be tissue specific, which warrants a more diverse mechanistic model applying to that specific tissue or cell type. This review presents the basic functions of the mitochondria and focuses on the complex interplay between oxidative stress, nitric oxide and uncoupling proteins in regulating mitochondria function with special focus on diabetes-induced alterations occurring on the mitochondria level.

  • 36.
    Friederich, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Johansson, Magnus
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Identification and distribution of uncoupling protein isoforms in the normal and diabetic rat kidney2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, p. 205-212Article in journal (Refereed)
    Abstract [en]

    Uncoupling protein (UCP)-2 and -3 are ubiquitously expressed throughout the body but there is currently no information regarding the expression and distribution of the different UCP isoforms in the kidney. Due to the known cross-reactivity of the antibodies presently available for detection of UCP-2 and -3 proteins, we measured the mRNA expression of UCP-1, -2 and -3 in the rat kidney in order to detect the kidney-specific UCP isoforms. Thereafter, we determined the intrarenal distribution of the detected UCP isoforms using immunohistochemistry. Thereafter, we compared the protein levels in control and streptozotocin-induced diabetic rats using Western blot. Expressions of the UCP isoforms were also performed in brown adipose tissue and heart as positive controls for UCP-1 and 3, respectively. UCP-2 mRNA was the only isoform detected in the kidney. UCP-2 protein expression in the kidney cortex was localized to proximal tubular cells, but not glomerulus or distal nephron. In the medulla, UCP-2 was localized to cells of the medullary thick ascending loop of Henle, but not to the vasculature or parts of the nephron located in the inner medulla. Western blot showed that diabetic kidneys have about 2.5-fold higher UCP-2 levels compared to controls. In conclusion, UCP-2 is the only isoform detectable in the kidney and UCP-2 protein can be detected in proximal tubular cells and cells of the medullary thick ascending loop of Henle. Furthermore, diabetic rats have increased UCP-2 levels compared to controls, but the mechanisms underlying this increase and its consequences warrants further studies.

  • 37.
    Friederich Persson, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    The Role of Mitochondrial Uncoupling in the Development of Diabetic Nephropathy2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Diabetes is closely associated with increased oxidative stress, especially originating from the mitochondria. A mechanism to reduce increased mitochondria superoxide production is to reduce the mitochondria membrane potential by releasing protons across the mitochondria membrane. This phenomenon is referred to as mitochondria uncoupling since oxygen is consumed independently of ATP being produced and can be mediated by Uncoupling Proteins (UCPs). However, increased oxygen consumption is potentially detrimental for the kidney since it can cause tissue hypoxia. Therefore, this thesis aimed to investigate the role of mitochondria uncoupling for development of diabetic nephropathy.

         UCP-2 was demonstrated to be the only isoform expressed in the kidney, and localized to tubular segments performing the majority of tubular electrolyte transport. Streptozotocin-induced diabetes in rats increased UCP-2 protein expression and correlated to increased non-transport dependent oxygen consumption in isolated proximal tubular cells. These effects were prevented by intense insulin treatment to the diabetic animals demonstrating a pivotal role of hyperglycemia. Importantly, elevated UCP-2 protein expression increased mitochondria uncoupling in mitochondria isolated from diabetic kidneys. Mitochondria uncoupling and altered morphology was also evident in kidneys from db/db-mice, a model of type-2 diabetes, together with proteinuria and glomerular hyperfiltration which are both clinical manifestations of diabetic nephropathy. Treatment with the antioxidant coenzyme Q10 prevented mitochondria uncoupling as well as morphological and functional alterations in these kidneys. Acute knockdown of UCP-2 paradoxically increased mitochondria uncoupling in a mechanism involving the adenosine nucleotide transporter. Increased uncoupling via adenosine nucleotide transporter decreased mitochondria membrane potential and kidney oxidative stress but did not affect glomerular filtration rate, renal blood flow, total kidney oxygen consumption or intrarenal tissue oxygen tension.

         The role of increased mitochondria oxygen consumption was investigated by administering the chemical uncoupler dinitrophenol to healthy rats. Importantly, increased mitochondria oxygen consumption resulted in kidney tissue hypoxia, proteinuria and increased staining of the tubular injury marker vimentin, demonstrating a crucial role of increased oxygen consumption per se and the resulting kidney tissue hypoxia for the development of nephropathy.

         Taken together, the data presented in this thesis establishes an important role of mitochondria uncoupling for the development of diabetic nephropathy.

    List of papers
    1. Identification and distribution of uncoupling protein isoforms in the normal and diabetic rat kidney
    Open this publication in new window or tab >>Identification and distribution of uncoupling protein isoforms in the normal and diabetic rat kidney
    Show others...
    2009 (English)In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, p. 205-212Article in journal (Refereed) Published
    Abstract [en]

    Uncoupling protein (UCP)-2 and -3 are ubiquitously expressed throughout the body but there is currently no information regarding the expression and distribution of the different UCP isoforms in the kidney. Due to the known cross-reactivity of the antibodies presently available for detection of UCP-2 and -3 proteins, we measured the mRNA expression of UCP-1, -2 and -3 in the rat kidney in order to detect the kidney-specific UCP isoforms. Thereafter, we determined the intrarenal distribution of the detected UCP isoforms using immunohistochemistry. Thereafter, we compared the protein levels in control and streptozotocin-induced diabetic rats using Western blot. Expressions of the UCP isoforms were also performed in brown adipose tissue and heart as positive controls for UCP-1 and 3, respectively. UCP-2 mRNA was the only isoform detected in the kidney. UCP-2 protein expression in the kidney cortex was localized to proximal tubular cells, but not glomerulus or distal nephron. In the medulla, UCP-2 was localized to cells of the medullary thick ascending loop of Henle, but not to the vasculature or parts of the nephron located in the inner medulla. Western blot showed that diabetic kidneys have about 2.5-fold higher UCP-2 levels compared to controls. In conclusion, UCP-2 is the only isoform detectable in the kidney and UCP-2 protein can be detected in proximal tubular cells and cells of the medullary thick ascending loop of Henle. Furthermore, diabetic rats have increased UCP-2 levels compared to controls, but the mechanisms underlying this increase and its consequences warrants further studies.

    Place, publisher, year, edition, pages
    New York: Springer, 2009
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-102380 (URN)10.1007/978-0-387-85998-9_32 (DOI)000262627100032 ()19227473 (PubMedID)978-0-387-85997-2 (ISBN)
    Conference
    Annual Conference of the International-Society-on-Oxygen-Transport-to-Tissue
    Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2017-12-13
    2. Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells
    Open this publication in new window or tab >>Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells
    Show others...
    2008 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1777, no 7-8, p. 935-940Article in journal (Refereed) Published
    Abstract [en]

    We have previously reported increased O(2) consumption unrelated to active transport by tubular cells and up-regulated mitochondrial uncoupling protein (UCP)-2 expressions in diabetic kidneys. It is presently unknown if the increased UCP-2 levels in the diabetic kidney results in mitochondrial uncoupling and increased O(2) consumption, which we therefore investigated in this study. The presence of UCP-2 in proximal tubular cells was confirmed by immunohistochemistry and found to be increased (western blot) in homogenized tissue and isolated mitochondria from kidney cortex of diabetic rats. Isolated proximal tubular cells had increased total and ouabain-insensitive O(2) consumption compared to controls. Isolated mitochondria from diabetic animals displayed increased glutamate-stimulated O(2) consumption (in the absence of ADP and during inhibition of the ATP-synthase by oligomycin) compared to controls. Guanosine diphosphate, an UCP inhibitor, and bovine serum albumin which removes fatty acids that are essential for UCP-2 uncoupling activity, independently prevented the increased glutamate-stimulated O(2) consumption in mitochondria from diabetic animals. In conclusion, diabetic rats have increased mitochondrial UCP-2 expression in renal proximal tubular cells, which results in mitochondrial uncoupling and increased O(2) consumption. This mechanism may be protective against diabetes-induced oxidative stress, but will increase O(2) usage. The subsequently reduced O(2) availability may contribute to diabetes-induced progressive kidney damage.

    Keyword
    Diabetes mellitus, kidney, mitochondria, uncoupling protein-2, oxygen consumption
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-110142 (URN)10.1016/j.bbabio.2008.03.030 (DOI)000257696400054 ()18439413 (PubMedID)
    Note
    Conference Information: 15th European Bioenergetic Conference Trinity Coll, Dublin, IRELAND, JUL 19-24, 2008 Available from: 2009-11-04 Created: 2009-11-04 Last updated: 2017-12-12Bibliographically approved
    3. Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db-mice as a model of type 2 diabetes
    Open this publication in new window or tab >>Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db-mice as a model of type 2 diabetes
    Show others...
    2012 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 5, p. 1535-1543Article in journal (Refereed) Published
    Abstract [en]

    Aims/hypothesis: Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes.

    Methods: Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment.

    Results: Untreated db/db mice displayed mitochondrial uncoupling, manifested as glutamate-stimulated oxygen consumption (2.7 +/- 0.1 vs 0.2 +/- 0.1 pmol O-2 s(-1) [mg protein](-1)), glomerular hyperfiltration (502 +/- 26 vs 385 +/- 3 mu l/min), increased proteinuria (21 +/- 2 vs 14 +/- 1, mu g/24 h), mitochondrial fragmentation (fragmentation score 2.4 +/- 0.3 vs 0.7 +/- 0.1) and size (1.6 +/- 0.1 vs 1 +/- 0.0 mu m) compared with untreated controls. All alterations were prevented or reduced by CoQ10 treatment. Mitochondrial uncoupling was partly inhibited by the UCP inhibitor GDP (-1.1 +/- 0.1 pmol O-2 s(-1) [mg protein](-1)). UCP-2 protein levels were similar in untreated control and db/db mice (67 +/- 9 vs 67 +/- 4 optical density; OD) but were reduced in CoQ10 treated groups (43 +/- 2 and 38 +/- 7 OD).

    Conclusions/interpretation: db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.

    Keyword
    db/db-mice, Kidney, Mitochondria, Type 2 diabetes, Uncoupling protein-2
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-167777 (URN)10.1007/s00125-012-2469-5 (DOI)000302994600036 ()
    Available from: 2012-02-01 Created: 2012-02-01 Last updated: 2018-01-12Bibliographically approved
    4. Acute knockdown of uncoupling protein-2 increases mitochondria uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys
    Open this publication in new window or tab >>Acute knockdown of uncoupling protein-2 increases mitochondria uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys
    Show others...
    2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e39635-Article in journal (Refereed) Published
    Abstract [en]

    Increased O2 metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O2 consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (−30–50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.

    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-167782 (URN)10.1371/journal.pone.0039635 (DOI)000305966500017 ()
    Available from: 2012-02-01 Created: 2012-02-01 Last updated: 2018-01-12Bibliographically approved
    5. Kidney function after in vivo gene silencing of Uncoupling Protein-2 in streptozotocin-induced diabetic rats
    Open this publication in new window or tab >>Kidney function after in vivo gene silencing of Uncoupling Protein-2 in streptozotocin-induced diabetic rats
    2013 (English)In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 765, p. 217-223Article in journal (Refereed) Published
    Abstract [en]

    Kidney uncoupling protein 2 (UCP-2) increases in streptozotocin-induced diabetes, resulting in mitochondria uncoupling, i.e., increased oxygen consumption unrelated to active transport. The present study aimed to investigate the role of UCP-2 for normal and diabetic kidney function utilizing small interference RNA (siRNA) to reduce protein expression. Diabetic animals had increased glomerular filtration rate and kidney oxygen consumption, resulting in decreased oxygen tension and transported sodium per consumed oxygen. UCP-2 protein levels decreased 2 and 50% after UCP-2 siRNA administration in control and diabetic animals respectively. Kidney function was unaffected by in vivo siRNA-mediated gene silencing of UCP-2. The reason for the lack of effect of reducing UCP-2 is presently unknown but may involve compensatory mitochondrial uncoupling by the adenosine nucleotide transporter.

    Place, publisher, year, edition, pages
    Springer-Verlag New York, 2013
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-167783 (URN)10.1007/978-1-4614-4989-8_30 (DOI)000339280100031 ()978-1-4614-4771-9 (ISBN)978-1-4614-4989-8 (ISBN)
    Available from: 2012-02-01 Created: 2012-02-01 Last updated: 2018-01-12
    6. Increased mitochondria uncoupling results in kidney tissue hypoxia and proteinuria.
    Open this publication in new window or tab >>Increased mitochondria uncoupling results in kidney tissue hypoxia and proteinuria.
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-167786 (URN)
    Available from: 2012-02-01 Created: 2012-02-01 Last updated: 2018-01-12
  • 38.
    Friederich Persson, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Aslam, Shakil
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Welch, William J.
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Wilcox, Christopher S.
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Acute knockdown of uncoupling protein-2 increases mitochondria uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e39635-Article in journal (Refereed)
    Abstract [en]

    Increased O2 metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O2 consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (−30–50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.

  • 39.
    Friederich Persson, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Franzén, Stephanie
    Catrina, Sergiu-Bogdan
    Karolinska Institutet, Institutionen för molekylär medicin och kirurgi.
    Dallner, Gustav
    Karolinska Institutet, Institutionen för molekylär medicin och kirurgi.
    Brismar, Kerstin
    Karolinska Institutet, Institutionen för molekylär medicin och kirurgi.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db-mice as a model of type 2 diabetes2012In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, no 5, p. 1535-1543Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes.

    Methods: Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment.

    Results: Untreated db/db mice displayed mitochondrial uncoupling, manifested as glutamate-stimulated oxygen consumption (2.7 +/- 0.1 vs 0.2 +/- 0.1 pmol O-2 s(-1) [mg protein](-1)), glomerular hyperfiltration (502 +/- 26 vs 385 +/- 3 mu l/min), increased proteinuria (21 +/- 2 vs 14 +/- 1, mu g/24 h), mitochondrial fragmentation (fragmentation score 2.4 +/- 0.3 vs 0.7 +/- 0.1) and size (1.6 +/- 0.1 vs 1 +/- 0.0 mu m) compared with untreated controls. All alterations were prevented or reduced by CoQ10 treatment. Mitochondrial uncoupling was partly inhibited by the UCP inhibitor GDP (-1.1 +/- 0.1 pmol O-2 s(-1) [mg protein](-1)). UCP-2 protein levels were similar in untreated control and db/db mice (67 +/- 9 vs 67 +/- 4 optical density; OD) but were reduced in CoQ10 treated groups (43 +/- 2 and 38 +/- 7 OD).

    Conclusions/interpretation: db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.

  • 40.
    Friederich Persson, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Nangaku, Masaomi
    University of Tokyo.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Increased mitochondria uncoupling results in kidney tissue hypoxia and proteinuria.Manuscript (preprint) (Other academic)
  • 41.
    Friederich-Persson, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Persson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nangaku, Masaomi
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Renal hypoxia due to increased oxygen metabolism is an independent pathway to nephropathy2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 890.6Article in journal (Other academic)
  • 42.
    Friederich-Persson, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Persson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Increased kidney metabolismas a pathway to kidney tissue hypoxia and damage: effects of triiodothyronine and dinitrophenol in normoglycemic rats2013In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 789, p. 9-14Article in journal (Refereed)
    Abstract [en]

    Intrarenal tissue hypoxia is an acknowledged common pathway to end-stage renal disease in clinically common conditions associated with development of chronic kidney disease, such as diabetes and hypertension. In diabetic kidneys, increased oxygen metabolism mediated by mitochondrial uncoupling results in decreased kidney oxygen tension (PO2) and contributes to the development of diabetic nephropathy. The present study investigated whether increased intrarenal oxygen metabolism per se can cause intrarenal tissue hypoxia and kidney damage, independently of confounding factors such as hyperglycemia and oxidative stress. Male Sprague-Dawley rats were untreated or treated with either triiodothyronine (T3, 10 g/kg bw/day, subcutaneously for 10 days) or the mitochondria uncoupler dinitrophenol (DNP, 30 mg/kg bw/day, oral gavage for 14 days), after which in vivo kidney function was evaluated in terms of glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Transonic, PAH clearance), cortical PO2 (Clark-type electrodes), kidney oxygen consumption (QO2), and proteinuria. Administration of both T3 and DNP increased kidney QO2 and decreased PO2 which resulted in proteinuria. However, GFR and RBF were unaltered by either treatment. The present study demonstrates that increased kidney metabolism per se can cause intrarenal tissue hypoxia which results in proteinuria. Increased kidney QO2 and concomitantly reduced PO2 may therefore be a mechanism for the development of chronic kidney disease and progression to end-stage renal disease.

  • 43.
    Friederich-Persson, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Welch, William J.
    Luo, Zaiming
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Angiotensin II Reduces Transport-Dependent Oxygen Consumption but Increases Transport-Independent Oxygen Consumption in Immortalized Mouse Proximal Tubular Cells2014In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 812, p. 157-163Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is closely associated with renal dysfunction following diabetes and hypertension. Angiotensin II (Ang II) can activate the NADPH-oxidase, increasing oxidative stress that is thought to blunt proximal tubular electrolyte transport and thereby oxygen consumption (QO(2)). We investigated the effect of Ang II on QO(2) in immortalized mouse proximal tubular cells over-expressing the NADPH oxidase subunit p22(phox); a model of increased oxidative stress. Cultured cells were exposed to either Ang II or H2O2 for 48 h. QO(2) was determined during baseline (113 mmol/l NaCl; transport-dependent QO(2)) and during sodium-free conditions (transport-independent QO(2)). Ang II reduced transport-dependent QO(2) in wild-types, but not in p22(phox) which also displayed increased QO(2) at baseline. Transport-independent QO(2) was increased in p22(phox) and Ang II had no additional effect, whereas it increased QO(2) in wild-type. Addition of H2O2 reduced transport-dependent QO(2) in wild-types, but not in p22(phox). Transport-independent QO(2) was unaffected by H2O2. The similar effects of Ang II and H2O2 to reduce transport-dependent QO(2) suggest a direct regulatory role of oxidative stress. In accordance, the transport-dependent QO(2) was reduced in p22(phox) already during baseline. The effects of Ang II on transport-independent QO(2) was not replicated by H2O2, indicating direct regulation via Ang II-receptors independently of oxidative stress. However, the Ang II effect was absent in p22(phox), suggesting that oxidative stress also modulates normal Ang II signaling. In conclusion, Ang II affects both transport-dependent and transport-independent QO(2) in proximal tubular cells and may be an important pathway modulating renal QO(2).

  • 44.
    Gao, Xiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Liu, Z. Z.
    Charite Univ Med Berlin, Inst Vegetat Physiol, Berlin, Germany..
    Mohammed, H.
    Charite Univ Med Berlin, Inst Vegetat Physiol, Berlin, Germany..
    Braun, D.
    Charite Univ Med Berlin, Inst Vegetat Physiol, Berlin, Germany..
    Zhuge, Z.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Liu, M.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Lai, E. Y.
    Zhejiang Univ, Dept Physiol, Hangzhou, Zhejiang, Peoples R China..
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlstrom, M.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Patzak, A.
    Charite Univ Med Berlin, Inst Vegetat Physiol, Berlin, Germany..
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Extravasal albumin concentration modulates contractile responses of renal afferent arterioles2018In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 222, no 2, article id e12925Article in journal (Refereed)
    Abstract [en]

    Aim: Afferent arterioles (AA) hold a key position in the regulation of renal blood flow and glomerular filtration rate. Being the effector site of tubuloglomerular feedback, the afferent arteriole contributes to the renal handling of sodium and fluid. Dehydration goes along with increased renal interstitial protein concentration. Here, the hypothesis was tested that extravasal protein concentration directly modulates afferent arteriolar tone, a mechanism which may contribute to body fluid volume control.

    Method: The effect of increased extravasal albumin concentration on the vascular reactivity was investigated in renal AA and interlobar arteries of mice, in rat renal AA and in pancreatic islet arterioles.

    Results: Albumin (2 and 4% in the bath solution) significantly potentiated the contractile response of renal afferent arterioles induced by angiotensin II and adenosine, as well as their combination, compared to the control situation (0.1% albumin). Albumin did not influence the contractility of larger renal vessels or pancreatic islet arterioles. Mimicking the increase in the osmolality induced by 4% albumin by applying mannitol to the bath solution also increased the response of renal arterioles to Ang II. However, the effect was smaller compared to that of albumin. The nitric oxide bioavailability, measured by DAF-FM fluorescence, was reduced in afferent arterioles exposed to 4% albumin.

    Conclusion: The protein-induced modulation of AA tone is mediated by the increased osmolality as well as by NO scavenging. The results suggest a possible contribution of these mechanisms to the control of extracellular fluid volume via adjustment of renal blood flow and glomerular filtration rate.

  • 45.
    Gao, Xiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Patzak, Andreas
    Sendeski, Mauricio
    Scheffer, Peter G.
    Teerlink, Tom
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Fredholm, Bertil B.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Adenosine A(1)-receptor deficiency diminishes afferent arteriolar and blood pressure responses during nitric oxide inhibition and angiotensin II treatment2011In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 301, no 6, p. R1669-R1681Article in journal (Refereed)
    Abstract [en]

    Adenosine mediates tubuloglomerular feedback responses via activation of A(1)-receptors on the renal afferent arteriole. Increased preglomerular reactivity, due to reduced nitric oxide (NO) production or increased levels of ANG II and reactive oxygen species (ROS), has been linked to hypertension. Using A(1)-receptor knockout (A(1)(-/-)) and wild-type (A(1)(+/+)) mice we investigated the hypothesis that A(1)-receptors modulate arteriolar and blood pressure responses during NO synthase (NOS) inhibition or ANG II treatment. Blood pressure and renal afferent arteriolar responses were measured in nontreated mice and in mice with prolonged N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME) or ANG II treatment. The hypertensive responses to L-NAME and ANG II were clearly attenuated in A(1)(-/-) mice. Arteriolar contractions to L-NAME (10(-4) mol/l; 15 min) and cumulative ANG II application (10(-12) to 10(-6) mol/l) were lower in A(1)(-/-) mice. Simultaneous treatment with tempol (10(-4) mol/l; 15 min) attenuated arteriolar responses in A(1)(+/+) but not in A(1)(-/-) mice, suggesting differences in ROS formation. Chronic treatment with L-NAME or ANG II did not alter arteriolar responses in A(1)(-/-) mice, but enhanced maximal contractions in A(1)(+/+) mice. In addition, chronic treatments were associated with higher plasma levels of dimethylarginines (asymmetrical and symmetrical) and oxidative stress marker malondialdehyde in A(1)(+/+) mice, and gene expression analysis showed reduced upregulation of NOS-isoforms and greater upregulation of NADPH oxidases. In conclusion, adenosine A(1)-receptors enhance preglomerular responses during NO inhibition and ANG II treatment. Interruption of A(1)-receptor signaling blunts L-NAME and ANG II-induced hypertension and oxidative stress and is linked to reduced responsiveness of afferent arterioles.

  • 46.
    Gao, Xiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Sallstrom, Johan
    Ma, Zufu
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Persson, Erik A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Role of Src homology 2 domain-containing protein B in the regulation of GFR and renal afferent arteriole responsiveness2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 1088.12Article in journal (Other academic)
  • 47.
    Gao, Xiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Yang, Ting
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Huang, Liyue
    Weitzberg, Eddie
    Lundberg, Jon
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Nitrite reduces angiotensin II-mediated contractions of the renal microcirculation by reducing NADPH oxidase activity and increasing nitric oxide bioavailability2013In: Nitric oxide, ISSN 1089-8603, E-ISSN 1089-8611, Vol. 31, no S1, p. S16-S17Article in journal (Other academic)
  • 48. Gerdts, Eva
    et al.
    Aksnes, Tonje A.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Kjeldsen, Sverre E.
    Os, Ingrid
    Ingrid Toft (June 2, 1959-April 26, 2014) OBITUARY2014In: Blood Pressure, ISSN 0803-7051, E-ISSN 1651-1999, Vol. 23, no 4, p. 255-255Article in journal (Refereed)
  • 49.
    Gonzalez Lindh, Margareta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Koyi, Hirsh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Blom Johansson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Research in Disability and Habilitation. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Högman, Marieann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Bendrik, Regina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Lisspers, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Ställberg, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    1.     Prevalence of subjective swallowing dysfunction in patients with stable COPD: Results from the TIE-study2017Conference paper (Other academic)
  • 50.
    Gonzalez Lindh, Margareta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Koyi, Hirsh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Blom Johansson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Research in Disability and Habilitation. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Högman, Marieann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Ställberg, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Bröms, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Swallowing dysfunction in COPD: Is it more related to burden of disease than lung function: Results from the TIE-study2017Conference paper (Other academic)
12345 1 - 50 of 226
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf