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  • 1.
    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)
  • 2. Bivol, Liliana Monica
    et al.
    Iversen, Bjarne Magnus
    Hultström, Michael
    Department of Clinical Science, University of Bergen, Norway.
    Wallace, Paal W
    Reed, Rolf Kåre
    Wiig, Helge
    Tenstad, Olav
    Unilateral renal ischemia in rats induces a rapid secretion of inflammatory markers to renal lymph and increased peritubular capillary permeability2015In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793Article in journal (Refereed)
    Abstract [en]

    A better understanding of the inflammatory process associated with renal ischemia-reperfusion (IR) injury may be clinically important. In this study we examined the role of the kidney in production of inflammatory mediators by analysing renal lymph after 30 min unilateral occlusion of renal artery followed by 120 min reperfusion, as well as the effect of IR on size selectivity for proteins in both glomerular and peritubular capillaries. All measured mediators increased dramatically in renal hilar lymph, whereas plasma and renal cortical tissue samples returned to control levels after 120 min reperfusion. The responses were differentiated; Interleukin-1β, monocyte chemoattractant protein-1 and leptin were markedly increased in plasma before reperfusion, reflecting an extrarenal response possibly induced by afferent renal nerve activity from the ischemic kidney. Tumour necrosis factor-α  was the only mediator showing elevated lymph to plasma ratio following 30 min reperfusion, indicating that most cytokines were released directly into the bloodstream. The IR induced rise in cytokine levels was paralleled by a significant increase in high molecular weight plasma proteins in both lymph and urine. The latter was shown as a 14-166 fold increase in glomerular sieving coefficient of plasma proteins assessed by a novel proteomic approach, and indicated a temporarily reduced size selectivity of both glomerular and peritubular capillaries. Collectively, our data suggest that cytokines from the ischemic kidney explain most of the rise in plasma concentration, and that the locally produced substances enter the systemic circulation through transport directly to plasma and not via the interstitium to lymph.

  • 3.
    Colldén, Jan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Birgisdottir, Birgitta
    Akad Sjukhuset, Uppsala, Sweden..
    Case of subdural hematoma after labor epidural: implications for follow-up of post dural puncture head ache2017In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 985-985Article in journal (Other academic)
  • 4. Dahl, Tone Dolva
    et al.
    Skogstrand, Trude
    Helle, Frank
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tenstad, Olav
    Iversen, Bjarne Magnus
    Attenuated contractility in afferent arterioles during development of proteinuria in two-kidney, one-clip hypertensive rats2013In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no S1, p. 1110.15-Article in journal (Other academic)
  • 5. Finne, Kenneth
    et al.
    Skogstrand, Trude
    Tenstad, Olav
    Berven, Frode
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vethe, Heidrun
    Vikse, Bjorn Egil
    Proteomic analysis of outer and juxtamedullary cortex of non-clipped kidneys in 2K1C hypertensive rats2013In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, no S1, p. 909.15-Article in journal (Other academic)
  • 6. 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)
  • 7. Graham, Lesley A
    et al.
    Padmanabhan, Sandosh
    Fraser, Niall J
    Kumar, Satish
    Bates, James M
    Raffi, Hajamohideen S
    Welsh, Paul
    Beattie, Wendy
    Hao, Shoujin
    Leh, Sabine
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Ferreri, Nicholas R
    Dominiczak, Anna F
    Graham, Delyth
    McBride, Martin W
    Validation of Uromodulin as a Candidate Gene for Human Essential Hypertension2014In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 63, no 3, p. 551-558Article in journal (Refereed)
    Abstract [en]

    A recent genome-wide association study identified a locus on chromosome 16 in the promoter region of the uromodulin (UMOD) gene that is associated with hypertension. Here, we examined the hypertension signal with functional studies in Umod knockout (KO) mice. Systolic blood pressure was significantly lower in KO versus wild-type (WT) mice under basal conditions (KO: 116.6±0.3 mm Hg versus WT: 136.2±0.4 mm Hg; P<0.0001). Administration of 2% NaCl did not alter systolic blood pressure in KO mice, whereas it increased in WT mice by ≈33%, P<0.001. The average 24-hour urinary sodium excretion in the KO was greater than that of WT mice (P<0.001). Chronic renal function curves demonstrate a leftward shift in KO mice, suggesting that the relationship between UMOD and blood pressure is affected by sodium. Creatinine clearance was increased during salt loading with 2% NaCl in the KO mice, leading to augmented filtered Na(+) excretion and further Na(+) loss. The difference in sodium uptake that exists between WT and KO strains was explored at the molecular level. Urinary tumor necrosis factor-α levels were significantly higher in KO mice compared with WT mice (P<0.0001). Stimulation of primary thick ascending limb of the loop of Henle cells with exogenous tumor necrosis factor-α caused a reduction in NKCC2A expression (P<0.001) with a concurrent rise in the levels of UMOD mRNA (P<0.001). Collectively, we demonstrate that UMOD regulates sodium uptake in the thick ascending limb of the loop of Henle by modulating the effect of tumor necrosis factor-α on NKCC2A expression, making UMOD an important determinant of blood pressure control.

  • 8. Helle, Frank
    et al.
    Skogstrand, Trude
    Schwartz, Idit F
    Schwartz, Doron
    Iversen, Bjarne Magnus
    Palm, Fredrik
    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.
    Nitric oxide in afferent arterioles after uninephrectomy depends on extracellular L-arginine2013In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 304, no 8, p. F1088-F1098Article in journal (Refereed)
    Abstract [en]

    Uninephrectomy (UNX) causes hyperperfusion of the contralateral remaining kidney via increased nitric oxide (NO) synthesis. Although the exact mechanism remains largely unknown, we hypothesize that this would be localized to the afferent arteriole and that it depends on cellular uptake of L-arginine. The experiments were performed in rats two days (early) or six weeks (late) after UNX and compared to controls (Sham) to study acute and chronic effects on NO metabolism. Renal blood flow was increased after UNX (21±2 ml/(min*kg) in sham, 30±3 in early, and 26±1 in late, P<0.05). NO inhibition with L-NAME caused a greater increase in renal vascular resistance in early UNX compared to Sham and late UNX (138±24% vs. 88±10% and 84±7%, P<0.01). The lower limit of autoregulation was increased both in early and late UNX compared to Sham (P<0.05). L-NAME did not affect the Ang II induced contraction of isolated afferent arterioles (AA) from Sham. AA from early UNX displayed a more pronounced contraction in response to L-NAME (-57±7% vs. -16±7%, P<0.05), and in the absence of L-arginine (-41±4%, P<0.05) compared to both late UNX and Sham. mRNA expression of endothelial NO synthase was reduced, whereas protein expression was unchanged. Cationic amino acid transporters-1 and -2 mRNA were increased, while protein was unaffected in isolated preglomerular resistance vessels. In conclusion, NO-dependent hyperperfusion of the remaining kidney in early UNX is associated with increased NO-release from the afferent arteriole which is highly dependent on extracellular L-arginine availability.

  • 9.
    Hultström, Michael
    Institutt for Indremedisin, Universitetet i Bergen.
    Angiotensin II in hypertension, renal damage and renal vascular function2010Doctoral thesis, comprehensive summary (Other academic)
    List of papers
    1. AT(1) receptor activation regulates the mRNA expression of CAT1, CAT2, arginase-1, and DDAH2 in preglomerular vessels from angiotensin II hypertensive rats.
    Open this publication in new window or tab >>AT(1) receptor activation regulates the mRNA expression of CAT1, CAT2, arginase-1, and DDAH2 in preglomerular vessels from angiotensin II hypertensive rats.
    2009 (English)In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 297, no 1, p. F163-8Article in journal (Refereed) Published
    Abstract [en]

    Previously, we found increased expression of l-arginine metabolizing enzymes in both kidneys from two-kidney, one-clip (2K1C) hypertensive rats (Helle F, Hultstrom M, Skogstrand T, Palm F, Iversen BM. Am J Physiol Renal Physiol 296: F78-F86, 2009). In the present study, we investigate whether AT(1) receptor activation can induce the changes observed in 2K1C. Four groups of rats were infused with 80 ng/min ANG II or saline for 14 days and/or given 60 mg x kg(-1) x day(-1) losartan. Gene expression was studied in isolated preglomerular vessels by RT-PCR. Dose-responses to ANG II were studied in isolated preglomerular vessels with and without acute NOS inhibition [10(-4) mol/l N(G)-nitro-l-arginine methyl ester (l-NAME)]. Expressions of endothelial nitric oxide synthase (eNOS), caveolin-1, and arginase-2 were not changed by ANG II infusion. CAT1 (0.3 8 +/- 0.07 to 0.73 +/- 0.12, P < 0.05), CAT2 (1.14 +/- 0.29 to 2.74 +/- 0.48), DDAH2 (1.09 +/- 0.27 to 2.3 +/- 0.46), and arginase-1 (1.08 +/- 0.17 to 1.82 +/- 0.22) were increased in ANG II-infused rats. This was prevented by losartan treatment, which reduced the expression of eNOS (0.97 +/- 0.26 to 0.37 +/- 0.11 in controls; 0.8 +/- 0.16 to 0.36 +/- 0.1 in ANG II-infused rats) and caveolin-1 (2.49 +/- 0.59 to 0.82 +/- 0.24 in controls and 2.59 +/- 0.61 to 1.1 +/- 0.25 in ANG II-infused rats). ANG II (10(-10) mol/l) caused vessels from ANG II-infused animals to contract to 53 +/- 15% of baseline diameter and 90 +/- 5% of baseline diameter in controls (P < 0.05) and was further enhanced by l-NAME to 4 +/- 4% of baseline diameter (P < 0.05). In vivo losartan treatment reduced the reactivity of isolated vessels to 91 +/- 2% of baseline in response to 10(-7) mol/l ANG II compared with 82 +/- 3% in controls (P < 0.05) and prevented the increased responsiveness caused by ANG II infusion. In conclusion, CAT1, CAT2, DDAH2, and arginase-1 expression in renal resistance vessels is regulated through the AT(1) receptor. This finding may be of direct importance for NOS and the regulation of preglomerular vascular function.

    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-170523 (URN)10.1152/ajprenal.00087.2009 (DOI)19386725 (PubMedID)
    Available from: 2012-07-02 Created: 2012-03-12 Last updated: 2018-01-12
    2. Angiotensin II-induced contraction is attenuated by nitric oxide in afferent arterioles from the nonclipped kidney in 2K1C
    Open this publication in new window or tab >>Angiotensin II-induced contraction is attenuated by nitric oxide in afferent arterioles from the nonclipped kidney in 2K1C
    Show others...
    2009 (English)In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 296, no 1, p. F78-F86Article in journal (Refereed) Published
    Abstract [en]

    Two-kidney, one-clip (2K1C) is a model of renovascular hypertension where we previously found an exaggerated intracellular calcium (Ca(i)(2+)) response to ANG II in isolated afferent arterioles (AAs) from the clipped kidney (Helle F, Vagnes OB, Iversen BM. Am J Physiol Renal Physiol 291: F140-F147, 2006). To test whether nitric oxide (NO) ameliorates the exaggerated ANG II response in 2K1C, we studied ANG II (10(-7) mol/l)-induced calcium signaling and contractility with or without the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME). In AAs from the nonclipped kidney, l-NAME increased the ANG II-induced Ca(i)(2+) response from 0.28 +/- 0.05 to 0.55 +/- 0.09 (fura 2, 340 nm/380 nm ratio) and increased contraction from 80 +/- 6 to 60 +/- 6% of baseline (P < 0.05). In vessels from sham and clipped kidneys, l-NAME had no effect. In diaminofluorescein-FM diacetate-loaded AAs from the nonclipped kidney, ANG II increased NO-derived fluorescence to 145 +/- 34% of baseline (P < 0.05 vs. sham), but not in vessels from the sham or clipped kidney. Endothelial NOS (eNOS) mRNA and ser-1177 phosphorylation were unchanged in both kidneys from 2K1C, while eNOS protein was reduced in the clipped kidney compared with sham. Cationic amino acid transferase-1 and 2 mRNAs were increased in 2K1C, indicating increased availability of l-arginine for NO synthesis, but counteracted by decreased scavenging of the eNOS inhibitor asymmetric dimethylarginine by dimethylarginine dimethylaminohydrolase 2. In conclusion, the Ca(i)(2+) and contractile responses to ANG II are blunted by NO release in the nonclipped kidney. This may protect the nonclipped kidney from the hypertension and elevated ANG II levels in 2K1C.

    Keywords
    two-kidney, one-clip, renovascular hypertension
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-102177 (URN)10.1152/ajprenal.90518.2008 (DOI)000262101200009 ()18945823 (PubMedID)
    Available from: 2009-05-05 Created: 2009-05-05 Last updated: 2017-12-13
    3. Prevention of hypertension and organ damage in 2-kidney, 1-clip rats by tetradecylthioacetic acid.
    Open this publication in new window or tab >>Prevention of hypertension and organ damage in 2-kidney, 1-clip rats by tetradecylthioacetic acid.
    Show others...
    2006 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 48, no 3, p. 460-6Article in journal (Refereed) Published
    Abstract [en]

    Dietary lipids are reported to affect the blood pressure in both humans and experimental animal models with hypertension. In the present study, 2-kidney, 1-clip (2K1C) hypertensive rats were treated with the modified fatty acid tetradecylthioacetic acid (TTA) from the time of clipping or after hypertension was established. TTA treatment attenuated the development of hypertension and reduced established 2K1C hypertension. The mRNA level of renin in the clipped kidney and the plasma renin activity were markedly reduced, and the plasma angiotensin II level tended to decrease after TTA treatment. In addition, TTA reduced the mRNA level of angiotensinogen in white adipose tissue. Prevention of organ damage was demonstrated by normal urinary excretion of protein, maintained serum albumin, lower heart weight, and clearly reduced vascular, glomerular, and tubulointerstitial damage in the nonclipped kidney. Renal function was not affected as estimated by unchanged plasma creatinine. Furthermore, the serum levels of triacylglycerol and cholesterol were reduced by TTA. The serum fatty acid composition was changed, resulting in a favorable increase of oleic acid. However, the levels of all of the omega-3 fatty acids and of linoleic acid were reduced, and no change was seen in the level of arachidonic acid, but the urinary excretion of 8-iso-prostaglandin F2alpha was declined. In conclusion, TTA attenuated the development of hypertension, reduced established hypertension, and prevented the development of organ damage in 2K1C rats, possibly by reducing the amounts of the vasoconstrictors angiotensin II and 8-iso-prostaglandin F2alpha and by inducing a favorable increase of oleic acid in serum.

    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-170526 (URN)10.1161/01.HYP.0000233018.60736.70 (DOI)16847149 (PubMedID)
    Available from: 2012-07-02 Created: 2012-03-12 Last updated: 2018-01-12
  • 10.
    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.
    Caloric restriction reduces age-related but not all-cause mortality2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 214, no 1, p. 3-5Article in journal (Other academic)
  • 11.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Development of structural kidney damage in spontaneously hypertensive rats2012In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 30, no 6, p. 1087-1091Article, review/survey (Refereed)
    Abstract [en]

    The spontaneously hypertensive rat (SHR) is one of the major models of hypertension. This article describes the current state of knowledge about the mechanism behind kidney damage in SHR in the context of human hypertension and hypertensive kidney disease. It will argue that hypertensive damage in the SHR is pressure-dependent and shows how initial vascular damage leads to a loss of autoregulation and arterial hypertrophy in the juxtamedullary cortex while the outer cortical structures are relatively protected. Progressive arteriolar media hypertrophy then leads to the collapse of some glomeruli followed by tubular atrophy. The reduced glomerular filtration, thus, leads to compensatory hyperfiltration in another population of glomeruli which develop proteinuria and glomerulosclerosis. This model provides some important questions for future research. The regulation of media hypertrophy will be of great interest, as it might slow nephron loss and interstitial fibrosis. Finally, the mechanism by which reduced tubular flow leads to tubular atrophy is another important area for future research. Initial findings indicate that cilia activation may be of major importance for maintaining tubular structure.

  • 12.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    In-common molecular pathway for six different etiologies of acute kidney injury2017In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 1041-1041Article in journal (Other academic)
  • 13.
    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.
    LACK OF EFFECT OF DIETARY NITRATE IN ELITE ATHLETES MAY BE DUE TO DILATION OF NON-PRIORITIZED VASCULAR BEDS2015In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 119, no 6, p. 762-762Article in journal (Refereed)
  • 14.
    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.
    Neurohormonal interactions on the renal oxygen delivery and consumption in haemorrhagic shock-induced acute kidney injury2013In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 209, no 1, p. 11-25Article, review/survey (Refereed)
    Abstract [en]

    Haemorrhagic shock is a common cause of acute kidney injury, which is a major risk factor for developing chronic kidney disease. The mechanism is superficially straightforward. An arterial pressure below the kidney's autoregulatory region leads to a direct reduction in filtration pressure and perfusion, which in turn cause renal failure with reduced glomerular filtration rate (GFR), and AKI because of hypoxia. However, the kidney's situation is further worsened by the hormonal and neural reactions to reduced perfusion pressure. There are three major systems working to maintain arterial pressure in shock: Sympathetic signaling, the renin-angiotensin-system, and vasopressin. These work to retain electrolytes and water, and to increase peripheral resistance and cardiac output. In the kidney the increased electrolyte reabsorption consumes oxygen. At the same time, at the signaling level seen in shock, all of these hormones reduces renal perfusion, and thereby oxygen delivery. This creates an exaggerated hypoxic situation that is liable to worsen the AKI. The present review will examine this mechanistic background and identify a number of areas that require further studies. At this time the ideal treatment of haemorrhagic shock appears to be slow fluid resuscitation, possibly with hyperosmolar sodium, low chloride, and no artificial colloids. From the standpoint of the kidney, renin-angiotensin system inhibitors appear fruitful for further study.

  • 15.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Njurarnas betydelse vid utveckling av essentiell hypertoni2012In: BestPractice, no 2, p. 8-9Article, review/survey (Other academic)
  • 16.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nyrenes betydning ved utvikling av essensiell hypertensjon2011In: BestPractice, no 1, p. 22-23Article, review/survey (Other academic)
  • 17.
    Hultström, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Aksnes, Tonje A.
    Gerdts, Eva
    Kjeldsen, Sverre E.
    Toft, Ingrid
    Bjarne Magnus Iversen (30 March 1942 – 5 August 2011)2011In: Blood Pressure, ISSN 0803-7051, E-ISSN 1651-1999, Vol. 20, no 5, p. 317-317Article in journal (Other academic)
  • 18.
    Hultström, Michael
    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 Surgical Sciences, Anaesthesiology and Intensive Care.
    Amorim de Paula, Cristiane
    Antônio Peliky Fontes, Marco
    Porcelli, Simone
    Bellistri, Giuseppe
    Pugliese, Lorenzo
    Rasica, Letizia
    Marzorati, Mauro
    Pavei, Gaspare
    Ferguson, Scott K
    Holdsworth, Clark T
    Musch, Timothy I
    Poole, David C
    Bourdillon, Nicolas
    Hoon, Matthew W
    Burke, Louise M
    Michielli, Donald W
    Faiss, Raphael
    Millet, Grégoire P
    Corona, Benjamin T
    Green, Michael S
    da Silveira, Anderson Luiz B
    Sindler, Amy L
    Casey, Darren P
    Johnson, Bruce D
    Wheatley, Courtney M
    Kunces, Laura J
    Bescos, Raul
    Cody, L C
    Martens, C R
    Justice, J N
    Ballak, S B
    Ballak, D B
    Wanner, Samuel Penna
    Rehman, Shabina
    Commentaries on Viewpoint: Can elite athletes benefit from dietary nitrate supplementation?2015In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 119, no 6, p. 762-769Article in journal (Refereed)
  • 19.
    Hultström, Michael
    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 Surgical Sciences, Anaesthesiology and Intensive Care.
    Becriovic-Agic, Mediha
    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.
    Comparison of acute kidney injury of different aetiology reveals in-common mechanisms of tissue damage2018In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 50, no 3, p. 127-141Article, review/survey (Refereed)
    Abstract [en]

    Acute kidney injury (AKI) is a syndrome of reduced glomerular filtration rate (GFR) and urine production caused by a number of different diseases. It is associated with renal tissue damage. This tissue damage can cause tubular atrophy and interstitial fibrosis that leads to nephron loss and progression of chronic kidney disease (CKD). This review describes the in-common mechanisms behind tissue damage in AKI caused by different underlying diseases. Comparing six high-quality microarray studies of renal gene expression after AKI in disease models (gram-negative sepsis, gram-positive sepsis, ischemia-reperfusion, malignant hypertension, rhabdomyolysis and cisplatin toxicity) identified 5254 differentially expressed genes in at least one of the AKI models. 66% of genes were only found in one model showing that there are unique features to AKI depending on the underlying disease. There were in-common features in the form of four genes that were differentially expressed in all six models, 49 in at least five, and 215 were in-common between at least four models. Gene ontology enrichment analysis could be broadly categorized into the injurious processes hypoxia, oxidative stress, and inflammation, as well as the cellular outcomes of cell death and tissue remodeling in the form of epithelial to mesenchymal transition (EMT). Pathway analysis showed that MYC is a central connection in the network of activated genes in-common to AKI, which suggests that it may be a central regulator of renal gene expression in tissue injury during AKI. The outlining of this molecular network may be useful for understanding progression from AKI to CKD.

  • 20.
    Hultström, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lai, En Yin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ma, Zufu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Källskog, Örjan
    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.
    Persson, A Erik G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Adenosine triphosphate increases the reactivity of the afferent arteriole to low concentrations of norepinephrine2007In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 293, no 6, p. R2225-R2231Article in journal (Refereed)
    Abstract [en]

    Adenosine triphosphate (ATP) and norepinephrine ( NE) interact in the control of blood flow in the kidney. A combined effect of NE and ATP has not been previously investigated at the level of the afferent arteriole (Af). We studied the effects of ATP on the contractile response of the Af to NE. Vascular reactivity to ATP, NE, and their combination was investigated in isolated perfused Af from mice. The roles of alpha-adrenoceptors and P2-ATP-receptors were investigated by use of specific agonists and antagonists. Cytosolic calcium was measured using the fluorescent calcium dye fura-2. ATP in concentrations from 10(-12) to 10(-4) mol/l induced transient contractions. NE constricted the Af in a dose-dependent manner and induced significant contractions at > 10(-7) mol/l. Treatment with ATP (10(-8) and 10(-6) mol/l) increased the NE response. Diameters were reduced by 20% already at 10(-11) mol/l NE during ATP treatment of 10(-6) mol/l. ATP increased the calcium response to NE significantly at 10(-8) and 10(-7)mol/l NE. The P2-type ATP receptor blocker pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) (10(-5) mol/l) abolished the sensitization of the NE response by ATP. The alpha(1)-blocker prazosin (10(-7) mol/l) inhibited the ATP effect, as did the alpha(2)-blocker yohimbine (10(-7) mol/l). Neither the phenylephrine- nor clonidine-induced concentration response curves was affected by ATP in the bath solution. Costimulation with ATP enhances the response of the Af to NE. This effect is mediated by increased cytosolic calcium. The enhancing effect involves P2-type ATP receptors and both alpha(1)- and alpha(2)-adrenoceptors.

  • 21.
    Hultström, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Leh, Sabine
    Paliege, Alexander
    Bachmann, Sebastian
    Skogstrand, Trude
    Iversen, Bjarne M.
    Collagen-binding proteins in age-dependent changes in renal collagen turnover: microarray analysis of mRNA expression2012In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, no 10, p. 576-586Article in journal (Refereed)
    Abstract [en]

    Aging is associated with progressive structural and functional deterioration of the kidney. Among the morphological changes associated with renal aging is an accumulation of extracellular matrix (ECM) in the glomeruli and tubuloinsterstitium, which may ultimately lead to the development of renal fibrosis. The mechanisms governing the regulation of ECM metabolism during renal aging are only incompletely defined. We present data from a genome-wide mRNA expression study on renal tissue from 90 wk old male Wistar rats and 10 wk old controls using Illumina BeadArray cDNA microarray. Regulation of candidate gene products was verified by real-time PCR. Morphological changes were evaluated by routine histological methods. Activated fibroblasts were identified by their expression of alpha-smooth muscle actin and collagen I. Morphological analysis demonstrated an expansion of the tubulointerstitial compartment with increased amounts of fibrous collagen but no overt glomerular or tubular damage in the aged rats. Activated fibroblasts were readily detectable in the adventitial layer of large renal vessels in controls and were not found in the old animals. In agreement with this finding, gene expression analysis revealed significant downregulation of collagen I mRNA along with numerous other ECM components. Concomitantly, collagen-stabilizing proteins were induced, whereas matrix metalloproteinase 9, an enzyme involved in collagen breakdown, was reduced. In conclusion, our results suggest that ECM expansion during renal aging results from an augmented stabilization in conjunction with a reduced breakdown of collagen fibers. Collagen stabilizing proteins may be essential for the control of renal ECM turnover and the pathogenesis of kidney fibrosis.

  • 22.
    Hultström, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Paliege, Alexander
    Skogstrand, Trude
    Faehling, Michael
    Nucleic acid binding of annexin A2 is regulated through angiotensin II/AT1 signaling in kidneys of hypertensive rats2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 1088.2Article in journal (Other academic)
  • 23.
    Hultström, Michael
    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 Surgical Sciences, Anaesthesiology and Intensive Care.
    Roxhed, Niclas
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Intradermal Insulin Delivery: A Promising Future for Diabetes Management2014In: Journal of Diabetes Science and Technology, E-ISSN 1932-2968, Vol. 8, no 3, p. 453-457Article in journal (Refereed)
    Abstract [en]

    The incidence of insulinopenic diabetes mellitus is constantly increasing, and in addition, approximately a third of all hyperinsulinemic diabetic patients develop insulinopenia. Optimal glycemic control is essential to minimize the risk for diabetes-induced complications, but the majority of diabetic patients fail to achieve proper long-term glucose levels even in clinical trials, and even more so in clinical practice. Compliance with a treatment regimen is likely to be higher if the procedure is simple, painless, and discreet. Thus, insulin has been suggested for nasal, gastrointestinal, and inhalation therapy, but so far with considerable downsides in effect, side effects, or patient acceptance. The stratum corneum is the main barrier preventing convenient drug administration without the drawbacks of subcutaneous injections. Recently, devices with miniaturized needles have been developed that combine the simplicity and discretion of patch-based treatments, but with the potential of peptide and protein administration. As this review describes, initial comparisons with subcutaneous administration now suggest microneedle patches for active insulin delivery are efficient in maintaining glycemic control. Hollow microneedle technology could also prove to be efficient in systemic as well as local delivery of other macromolecular drugs, such as vaccines.

  • 24. Iversen, Bjarne M.
    et al.
    Helle, Frank
    Hultström, Michael
    Skogstrand, Trude
    Nitrogen oxyd (NO) og nyrearteriestenose2008In: Nefrologisk forum, Vol. 14, no 2, p. 6-9Article, review/survey (Other academic)
  • 25. Jonsson, Sofia
    et al.
    Agic, Mediha Becriovic
    Tveitaras, Maria
    Skogstrand, Trude
    Karlsen, Tine
    Liden, Asa
    Leh, Sabine
    Iversen, Bjarne
    Reed, Rolf
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lower oxidative stress is associated with angiotensin II and salt-induced acute cardiorenal failure in BalbC mice but not C57Black62014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 860.10Article in journal (Other academic)
  • 26.
    Jönsson, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Agic, Mediha Becriovic
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tveitaras, Maria
    Univ Bergen, Dept Biomed, Bergen, Norway..
    Skogstrand, Trude
    Univ Bergen, Dept Biomed, Bergen, Norway..
    Karlsen, Tine V.
    Univ Bergen, Dept Biomed, Bergen, Norway..
    Lidén, Åsa
    Univ Bergen, Dept Biomed, Bergen, Norway..
    Leh, Sabine
    Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway..
    Iversen (Late), Bjarne M.
    Univ Bergen, Inst Med, Bergen, Norway..
    Reed, Rolf K.
    Univ Bergen, Dept Biomed, Bergen, Norway..
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Univ Bergen, Dept Biomed, Bergen, Norway..
    C57BL/6J mice are resistant to cardiorenal syndrome during high-salt and Angiotensin II treatment compared to Balb/c because of higher oxidative stress2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, p. 85-85Article in journal (Other academic)
  • 27.
    Jönsson, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Becirovic Agic, Mediha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Narfström, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Melville, Jacqueline M
    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.
    Renal neurohormonal regulation in heart failure decompensation2014In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 307, no 5, p. 493-497Article in journal (Refereed)
    Abstract [en]

    Decompensation in heart failure occurs when the heart fails to balance venous return with cardiac output, leading to fluid congestion, and contributing to mortality. Decompensated heart failure can cause acute kidney injury (AKI), which further increases mortality. Heart failure activates signaling systems that are deleterious to kidneys such as renal sympathetic nerve activity (RSNA), renin-angiotensin-aldosterone system and vasopressin secretion. All three reduce renal blood flow (RBF) and increase tubular sodium reabsorption, which may increase renal oxygen consumption causing AKI through renal tissue hypoxia. Vasopressin contributes to venous congestion through aquaporin-mediated water retention. Additional water retention may be mediated through vasopressin-induced medullary urea transport and hyaluronan, but needs further study. In addition, there are several systems that could protect the kidneys and reduce fluid retention such as natriuretic peptides, prostaglandins and nitric oxide. However, the effect of natriuretic peptides and nitric oxide are blunted in decompensation, partly due to oxidative stress. This review considers how neurohormonal signaling in heart failure drives fluid retention by the kidneys and thus exacerbates decompensation. It further identifies areas where there is limited data, such as signaling systems 20-HETE, purines, endothelin, the role of renal water retention mechanisms for congestion and renal hypoxia in AKI during heart failure.

  • 28.
    Jönsson, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Melville, Jacqueline
    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.
    Norepinephrine effects are not affected by Losartan in rats after resuscitated haemorrhage2017In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 963-963Article in journal (Other academic)
  • 29.
    Jönsson, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Melville, Jacqueline M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Agic, Mediha Becriovic
    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.
    Losartan does not decrease renal oxygenation and norepinephrine effects in rats after resuscitated hemorrhage.2018In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 315, no 2, p. F241-F246Article in journal (Refereed)
    Abstract [en]

    Renin-angiotensin-system blockers are thought to increase the risk of acute kidney injury after surgery and hemorrhage. We found that losartan does not cause renal cortical hypoxia after hemorrhage in rats because of decreased renal vascular resistance, but we did not evaluate resuscitation. We aimed to study losartan's effect on renal cortical and medullary oxygenation, as well as norepinephrine's vasopressor effect in a model of resuscitated hemorrhage. After 7 days of losartan (60 mg·kg-1·day-1) or control treatment, male Wistar rats were hemorrhaged 20% of their blood volume and resuscitated with Ringer's acetate. Mean arterial pressure, renal blood flow, and kidney tissue oxygenation were measured at baseline and after resuscitation. Finally, the effect of norepinephrine on mean arterial pressure and renal blood flow was investigated. As expected, losartan lowered mean arterial pressure but not renal blood flow. Losartan did not affect renal oxygen consumption and oxygen tension. Mean arterial pressure and renal blood flow were lower after resuscitated hemorrhage. A smaller increase of renal vascular resistance in the losartan group translated to a smaller decrease in cortical oxygen tension, but no significant difference was seen in medullary oxygen tension, either between groups or after hemorrhage. The effect of norepinephrine on mean arterial pressure and renal blood flow was similar in control- and losartan-treated rats. Losartan does not decrease renal oxygenation after resuscitated hemorrhage because of a smaller increase in renal vascular resistance. Further, losartan does not decrease the efficiency of norepinephrine as a vasopressor, indicating that blood pressure may be managed effectively during losartan treatment.

  • 30. Knapik, Piotr
    et al.
    Krzych, Łukasz J
    Weigl, Wojciech
    Adamski, Jan
    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.
    Mortality rate in Polish intensive care units is lower than predicted according to the APACHE II scoring system.2017In: Intensive Care Medicine, ISSN 0342-4642, E-ISSN 1432-1238, Vol. 43, p. 1745-1746Article in journal (Other academic)
  • 31.
    Melville, Jacqueline M.
    et al.
    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. Linkoping Univ, Dept Med & Hlth Sci, S-58183 Linkoping, Sweden..
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Angiotensin II AT1-receptor blockade using Losartan does not impair renal oxygenation following hemorrhage2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, p. 58-58Article in journal (Other academic)
  • 32.
    Melville, Jaqueline M
    et al.
    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.
    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.
    Renal oxygenation during haemorrhage is not aggravated by angiotensin II AT1-receptor blockade2016In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 216, no 2, p. 153-155Article in journal (Refereed)
  • 33.
    Peng, Di
    et al.
    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.
    Cupples, Claire
    Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC, Canada..
    Cupples, Will
    Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC, Canada..
    Mitrou, Nicholas
    Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC, Canada..
    Macrophage infiltration in the kidney after prolonged surgery with anesthesia2017In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 1010-1011Article in journal (Other academic)
  • 34. Skogstrand, Trude
    et al.
    Leh, Sabine
    McClure, John
    Dashti, Mohammed
    Iversen, Bjarne M
    Graham, Delyth
    McBride, Martin W
    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.
    Identification of a common molecular pathway in hypertensive renal damage: comparison of rat and human gene expression profiles2015In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 33, no 3, p. 584-596Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There is a common structural progression in hypertensive renal damage with early arterial damage and fibrosis in the juxtamedullary cortex.

    METHOD: The present investigation identifies a common pathway using three-gene expression profiles from hypertensive rat models: 60-week-old spontaneously hypertensive rat (SHR), salt-loaded stroke-prone SHR (SHRSP), and the non-clipped kidney after 24 weeks of two-kidney, one-clip hypertension (2K1C). Kidney damage was scored using a specialized system. Gene-expression profiles were determined using microarrays and validated using a panel of 47 genes by quantitative real-time PCR.

    RESULTS: All groups showed kidney damage (SHRs: 0.32 ± 0.09 vs. Wistar-Kyoto rats: 0.06 ± 0.03; 2K1C: 0.27 ± 0.13 vs. pooled controls: 0.01 ± 0.01; SHRSP: 1.13 ± 0.14 vs. WKY: 0.04 ± 0.03; all P < 0.05). A total of 1614 genes were changed in the SHR experiment, 1323 in the SHRSP, and 576 in the 2K1C. Eighty-eight genes were similarly regulated in all three models. Gene ontology enrichment analysis identified 59 ontologies that were enriched in all three datasets. These included over-representation to extracellular matrix, response to oxidative stress, and immune system processes. Out of the 88 in-common genes, 40 could be connected in a common pathway that was compared to two gene-expression profiles from human kidneys with histologically verified fibrosis to identify a highly significant number of in-common genes that were also represented in the common genetic pathway.

    CONCLUSION: There is a common pathway during the development of hypertensive kidney damage in rats irrespective of model. Interestingly, large parts of this common pathway are conserved in human kidney damage, which may indicate a broader importance in the development of chronic kidney disease.

  • 35. Skogstrand, Trude
    et al.
    Leh, Sabine
    Paliege, Alexander
    Reed, Rolf K.
    Vikse, Bjorn E.
    Bachmann, Sebastian
    Iversen, Bjarne M.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Arterial damage precedes the development of interstitial damage in the nonclipped kidney of two-kidney, one-clip hypertensive rats2013In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 31, no 1, p. 152-159Article in journal (Refereed)
    Abstract [en]

    Background: The progression of damage in the renal cortex has not been investigated in the nonclipped kidney of the two-kidney, one-clip model of renal hypertension. In other hypertensive models, damage has been found to progress from the juxtamedullary cortex (JMC) and outward, which has been attributed to early vascular effects. Method: The present study investigated the relation between perivascular deposition of collagen and structural damage after 16 and 24 weeks of hypertension in the nonclipped kidney in rats. Results: Periarterial collagen density in the kidney was significantly increased already 16 weeks after clipping, at that time tubulointerstitial damage was not evident. After 24 weeks of clipping, periarterial collagen was further increased, and tubulointerstitial damage had developed in the JMC, whereas the outer cortex was protected. Interstitial collagen was not significantly increased in any cortex part during the course of the experiment. Collagen type I a1 mRNA was increased in the JMC after 24 weeks, and alpha smooth muscle actin histochemistry and collagen type I a2 in-situ hybridization identified myofibroblasts around the arteries after 16 and 24 weeks as the major source of this increase. Conclusion: Fibrosis in the nonclipped kidney of renal hypertensive rats starts around the juxtamedullary resistance vessels and then progresses in the JMC, whereas the outer cortex is protected. This suggests that pressure-induced injury to the vasculature attracts or activates fibroblasts in the perivascular area, which may allow damage to progress by impairing vessel function.

  • 36. Skogstrand, Trude
    et al.
    McBride, Martin
    McClure, John
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Renal extracellular matrix in three rat-models of hypertensive kidney damage: A microarray study of SHR, SHRSP and 2K1C2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26Article in journal (Other academic)
  • 37. Tveitaras, Maria Kathrine
    et al.
    Skogstrand, Trude
    Helle, Frank
    Leh, Sabine
    Reed, Rolf K.
    Chatziantoniou, Christos
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    MMP2 deficient mice are protected from hydronephrosis after unilateral urethral obstruction2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26Article in journal (Other academic)
  • 38. Tveitarås, Maria K
    et al.
    Skogstrand, Trude
    Leh, Sabine
    Helle, Frank
    Iversen, Bjarne M
    Chatziantoniou, Christos
    Reed, Rolf K
    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.
    Matrix Metalloproteinase-2 Knockout and Heterozygote Mice Are Protected from Hydronephrosis and Kidney Fibrosis after Unilateral Ureteral Obstruction2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, article id e0143390Article in journal (Refereed)
    Abstract [en]

    Matrix Metalloproteinase-2 (Mmp2) is a collagenase known to be important in the development of renal fibrosis. In unilateral ureteral obstruction (UUO) the obstructed kidney (OK) develops fibrosis, while the contralateral (CL) does not. In this study we investigated the effect of UUO on gene expression, fibrosis and pelvic remodeling in the kidneys of Mmp2 deficient mice (Mmp2-/-), heterozygous animals (Mmp2+/-) and wild-type mice (Mmp2+/+). Sham operated animals served as controls (Cntrl). UUO was prepared under isoflurane anaesthesia, and the animals were sacrificed after one week. UUO caused hydronephrosis, dilation of renal tubules, loss of parenchymal thickness, and fibrosis. Damage was most severe in Mmp2+/+ mice, while both Mmp2-/- and Mmp2+/- groups showed considerably milder hydronephrosis, no tubular necrosis, and less tubular dilation. Picrosirius red quantification of fibrous collagen showed 1.63±0.25% positivity in OK and 0.29±0.11% in CL (p<0.05) of Mmp2+/+, Mmp2-/- OK and Mmp2-/- CL exhibited only 0.49±0.09% and 0.23±0.04% (p<0.05) positivity, respectively. Mmp2+/- OK and Mmp2+/- CL showed 0.43±0.09% and 0.22±0.06% (p<0.05) positivity, respectively. Transcriptomic analysis showed that 26 genes (out of 48 examined) were differentially expressed by ANOVA (p<0.05). 25 genes were upregulated in Mmp2+/+ OK compared to Mmp2+/+ CL: Adamts1, -2, Col1a1, -2, -3a1, -4a1, -5a1, -5a2, Dcn, Fbln1, -5, Fmod, Fn1, Itga2, Loxl1, Mgp, Mmp2, -3, Nid1, Pdgfb, Spp1, Tgfb1, Timp2, Trf, Vim. In Mmp2-/- and Mmp2+/- 18 and 12 genes were expressed differentially between OK and CL, respectively. Only Mmp2 was differentially regulated when comparing Mmp2-/- OK and Mmp2+/- OK. Under stress, it appears that Mmp2+/- OK responds with less Mmp2 upregulation than Mmp2+/+ OK, suggesting that there is a threshold level of Mmp2 necessary for damage and fibrosis to occur. In conclusion, reduced Mmp2 expression during UUO protects mice against hydronephrosis and renal fibrosis.

  • 39. Vethe, Heidrun
    et al.
    Finne, Kenneth
    Skogstrand, Trude
    Vaudel, Marc
    Vikse, Bjorn Egil
    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.
    Placier, Sandrine
    Scherer, Andreas
    Tenstad, Olav
    Marti, Hans-Peter P.
    DIFFERENTIAL PROTEOMICS OF EXPERIMENTAL HYPERTENSIVE RENAL DISEASE REVEALS DISTINCT PROTEIN SIGNATURES AND PERIOSTIN AS A DAMAGE MARKER2014In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 29, p. 201-201Article in journal (Other academic)
  • 40. Vethe, Heidrun
    et al.
    Finne, Kenneth
    Skogstrand, Trude
    Vaudel, Marc
    Vikse, Bjørn E
    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.
    Placier, Sandrine
    Scherer, Andreas
    Tenstad, Olav
    Marti, Hans-Peter
    Distinct protein signature of hypertension-induced damage in the renal proteome of the two-kidney, one-clip rat model2015In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 33, no 1, p. 126-135Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Hypertensive nephrosclerosis is one of the most frequent causes of chronic kidney failure. Proteome analysis potentially improves the pathophysiological understanding and diagnostic precision of this disorder. In the present exploratory study, we investigated experimental nephrosclerosis in the two-kidney, one-clip (2K1C) hypertensive rat model.

    METHODS:

    The renal cortex proteome from juxtamedullary cortex and outer cortex of 2K1C male Wistar-Hannover rats (n = 4) was compared with the sham-operated controls (n = 6), using mass spectrometry-based quantitative proteomics. We combined a high abundant plasma protein depletion strategy with an extended liquid chromatographic gradient to improve peptide and protein identification. Immunohistology was used for independent confirmation of abundance.

    RESULTS:

    We identified 1724 proteins, of which 1434 were quantified with at least two unique peptides. Comparative proteomics revealed 608 proteins, including the platelet-derived growth factor receptor-β signalling pathway, with different abundances between the non-clipped kidney of hypertensive 2K1C rats and the corresponding kidney of the normotensive controls (P < 0.05, absolute fold change ≥1.5). Among the most significantly altered proteins in the whole cortex were periostin, transgelin, and creatine kinase B-type. Relative abundance of periostin alone allowed clear classification of 2K1C and controls. Enrichment of periostin in 2K1C rats was verified by immunohistology, showing positivity especially around the fibrotic vessels.

    CONCLUSION:

    The proteome is altered in hypertension-induced kidney damage. We propose periostin, especially in combination with transgelin and creatine kinase B-type, as possible proteomic classifier to distinguish hypertensive nephrosclerosis from the normal tissue. This classifier needs to be further validated with respect to early diagnosis of fibrosis, prognosis, and its potential as a novel molecular target for pharmacological interventions.

  • 41.
    Wang, R
    et al.
    Jilin Normal Univ, Sch Life Sci, Dept Biotechnol, Siping, Peoples R China.
    Zhang, W
    Zhejiang Univ, Dept Physiol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China.
    Dong, Z
    Harbin Med Univ, Affiliated Hosp 1, Dept Cardiol, Harbin, Peoples R China.
    Qi, Y
    Jilin Normal Univ, Sch Life Sci, Dept Biosci, Siping, Peoples R China.
    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.
    Zhou, X
    Jilin Normal Univ, Sch Life Sci, Dept Biosci, Siping, Peoples R China.
    Lai, E Y
    Zhejiang Univ, Dept Physiol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China.
    c-Jun N-terminal Kinase mediates prostaglandin-induced sympathoexcitation in rats with chronic heart failure by reducing GAD1 and GABRA1 expression2017In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 219, no 2, p. 494-509Article in journal (Refereed)
    Abstract [en]

    AIM: Prostaglandin E2 mediates sympathoexcitation in chronic heart failure (CHF) through EP3 receptors (PTGER3) in the paraventricular nucleus (PVN). The aim of this study was to investigate the role of c-Jun N-terminal kinase (JNK) in expressional regulation of gamma-aminobutyric acid signalling in PVN in CHF rats.

    METHODS: Chronic heart failure was induced by left coronary ligation in Wistar rats. Renal sympathetic nerve discharge (RSND) and mean arterial pressure (MAP) responses to the PVN infusion were determined in anaesthetized rats. Osmotic minipumps were used for chronic PVN infusion. PTGER3 expression was examined with immunofluorescence staining, quantitative real-time PCR and Western blot.

    RESULTS: Chronic heart failure rats had increased JNK activation and decreased glutamate decarboxylase 1 (GAD1) and GABAA receptor alpha 1 subunit (GABRA1) expression in the PVN. PVN infusion of the PTGER3 agonist SC-46275 caused sympathoexcitation in sham-operated control (Sham) rats and increased it further in CHF. The PTGER3 antagonist L798106 reduced sympathoexcitation and cardiac dysfunction in CHF. PVN infusion of EP1 receptor antagonist SC-19220, EP2 receptor antagonist AH6809 or EP4 receptor antagonist L-161982 had no effect on sympathoexcitation. The JNK inhibitor SP600125 normalized sympathoexcitation and GAD1 and GABRA1 expression in PVN in CHF rats. Both the p44/42 and p38 mitogen-activated protein kinase inhibitors PD98059 and SB203580 could not prevent the downregulation of GAD1 and GABRA1 expression in PVN in CHF. PTGER3 agonist activated JNK but downregulated GAD1 and GABRA1 expression in NG108 neuronal cells.

    CONCLUSION: Prostaglandin signalling through upregulated PTGER3 activates JNK which reduces GAD1 and GABRA1 expression in the PVN, and contributes to sympathoexcitation in CHF.

  • 42. Wang, Renjun
    et al.
    Huang, Qian
    Zhou, Rui
    Dong, Zengxiang
    Qi, Yunfeng
    Li, Hua
    Wei, Xiaowei
    Wu, Hui
    Wang, Huiping
    Wilcox, Christopher S
    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.
    Zhou, Xiaofu
    Lai, En Yin
    Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus2016In: Circulation Heart Failure, ISSN 1941-3289, E-ISSN 1941-3297, Vol. 9, no 1, article id e002261Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chronic heart failure (CHF) increases sympathoexcitation through angiotensin II (ANG II) receptors (AT1R) in the paraventricular nucleus (PVN). Recent publications indicate both γ-aminobutyric acid B-type receptor 1 (GABBR1) and microRNA-7b (miR-7b) are expressed in the PVN. We hypothesized that ANG II regulates sympathoexcitation through homeobox D10 (HoxD10), which regulates miR-7b in other tissues.

    METHODS AND RESULTS: Ligation of the left anterior descendent coronary artery in rats caused CHF and sympathoexcitation. PVN expression of AT1R, HoxD10, and miR-7b was increased, whereas GABBR1 was lower in CHF. Infusion of miR-7b in the PVN caused sympathoexcitation in control animals and enhanced the changes in CHF. Antisense miR-7b infused in PVN normalized GABBR1 expression while attenuating CHF symptoms, including sympathoexcitation. A luciferase reporter assay detected miR-7b binding to the 3' untranslated region of GABBR1 that was absent after targeted mutagenesis. ANG II induced HoxD10 and miR-7b in NG108 cells, effects blocked by AT1R blocker losartan and by HoxD10 silencing. miR-7b transfection into NG108 cells decreased GABBR1 expression, which was inhibited by miR-7b antisense. In vivo PVN knockdown of AT1R attenuated the symptoms of CHF, whereas HoxD10 overexpression exaggerated them. Finally, in vivo PVN ANG II infusion caused dose-dependent sympathoexcitation that was abrogated by miR-7b antisense and exaggerated by GABBR1 silencing.

    CONCLUSIONS: There is an ANG II/AT1R/HoxD10/miR-7b/GABBR1 pathway in the PVN that contributes to sympathoexcitation and deterioration of cardiac function in CHF.

  • 43. Wang, Zhongli
    et al.
    Xu, Ming
    Hu, Zhengguo
    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.
    Lai, Enyin
    Sex-specific prevalence of fatty liver disease and associated metabolic factors in Wuhan, south central China2014In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 26, no 9, p. 1015-1021Article in journal (Refereed)
    Abstract [en]

    Background This study aimed to investigate the sex-specific prevalence and metabolic risk factors of fatty liver disease (FLD), and to predict the prevalence of steatohepatitis with liver fibrosis in Wuhan, south central China. Methods A cross-sectional study was conducted among 25 032 participants who underwent health checkups from 2010 to 2011 in Zhongnan hospital. Results The prevalence of FLD was higher among men than among women (31.8 vs. 12.9%, P<0.0001). However, it increased markedly with age among women, and in the age-groups above 60 years, the prevalence was similar between men and women (26.4 vs. 27.6%, P>0.05). FLD was associated with obesity, increased levels of total cholesterol, triglycerides (TG), low-density lipoproteins, serum uric acid, aspartate aminotransferase, alanine aminotransferase, and fasting blood sugar, an aspartate aminotransferase/alanine aminotransferase ratio of less than 1, and a decreased level of high-density lipoprotein in both sexes. Multiple regression analyses showed that obesity, elevated levels of fasting blood sugar, TG, total cholesterol, and alanine aminotransferase, an aspartate aminotransferase/alanine aminotransferase ratio of less than 1, serum uric acid levels, and decreased high-density lipoprotein levels were related to FLD in men, whereas age played a more prominent role in women. The prevalence of steatohepatitis with advanced fibrosis, estimated using the BMI, age, ALT, and TG index (BAAT index), was 2.5% in men and 1.4% in women; more women with FLD had a BAAT score of 3 or higher compared with men (9.0 vs. 6.6%). Conclusion The prevalence of FLD in China is high among men and elderly women and is mainly related to various metabolic parameters. The prevalence of steatohepatitis with advanced fibrosis is considerably high among individuals with FLD.

  • 44. Wang, Zhongli
    et al.
    Xu, Ming
    Peng, Jianhong
    Jiang, Li
    Hu, Zhengguo
    Wang, Hua
    Zhou, Shiqing
    Zhou, Rui
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lai, En Yin
    Prevalence and associated metabolic factors of fatty liver disease in the elderly2013In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 48, no 8, p. 705-709Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to investigate the metabolic risk factors for fatty liver disease in the elderly, and determine the prevalence of fatty liver disease in the elderly in Wuhan, central China.

    METHODS: The study was a case-control study based on all 4226 adults above 60years of age from a cohort investigated in 2010-11 at the medical examination center of Zhongnan hospital, using 3145 randomly selected adults under 60years of age from the same cohort as controls. Fatty liver disease (FLD) was identified with ultrasound imaging. The risk factors measured were body mass index (BMI), and plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low density lipoprotein (LDL) and serum uric acid (SUA). The probability of steatohepatitis with advanced fibrosis was predicted using a score based on BMI, age, ALT, and TG (BAAT),and using AST/ALT ratio (AAR).

    RESULTS: FLD was higher in the elderly (26.7%) than in the non-elderly (22.8%) and similar in the elderly between men and women (26.6% vs 27.0%, p>0.05). BMI, TC, TG, LDL, SUA, AST and ALT were all significantly higher in FLD, whereas the level of HDL was markedly lower. Multiple regression analyses showed that obesity, high TC, TG, SUA, low HDL, and elevated ALT, AAR<1 were closely related to the elderly FLD, while male sex, obesity, high TC, TG, low HDL, elevated ALT, AST and AAR<1 were closely related to the non-elderly FLD. The prevalence of steatohepatitis with advanced fibrosis estimated as BAAT index≥3 was 2.4% in all subjects, and was higher in the elderly FLD patients than in the non-elderly FLD patients.

    CONCLUSION: The prevalence of FLD is higher in the elderly, and is broadly related to the same metabolic risk factors as in the non-elderly. However, female-sex is no longer protective with increasing age, and the prevalence of steatohepatitis with advanced fibrosis is estimated to be considerably higher in the elderly FLD patients than in the non-elderly FLD controls.

  • 45.
    Weigl, Wojciech
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Adamski, Jan
    Satakunta Dist Hosp, Dept Anaesthesia & Intens Care, Pori, Finland..
    Gorynski, Pawel
    Natl Inst Publ Hlth, Natl Inst Hyg, Ctr Monitoring & Anal Populat Hlth Status, Warsaw, Poland..
    Kanski, Andrzej
    Med Univ Warsaw, Cent Teaching Hosp, Dept Anesthesiol & Intens Care 2, Warsaw, Poland..
    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.
    Comparison of ICU outcomes in Poland to other European countries: reasons for high mortality rates2017In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 61, no 8, p. 1022-1023Article in journal (Other academic)
1 - 45 of 45
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