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  • 51.
    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)
  • 52.
    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)
  • 53.
    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.

  • 54.
    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).

  • 55.
    Fähling, Michael
    et al.
    Charite, Inst Vegetat Physiol, Berlin, Germany.
    Paliege, Alexander
    Charite, Inst Anat, Berlin, Germany.
    Jönsson, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Becriovic Agic, Mediha
    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.
    Skogstrand, Trude
    Univ Bergen, Dept Biomed, Bergen, Norway.
    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.
    NFAT5 regulates renal gene expression in response to angiotensin II through Annexin-A2-mediated posttranscriptional regulation in hypertensive rats2019In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 316, no 1, p. F101-F112Article in journal (Refereed)
    Abstract [en]

    The aim was to identify new targets that regulate gene expression at the posttranscriptional level in angiotensin II (ANGII)-mediated hypertension. Heparin affinity chromatography was used to enrich nucleic acid-binding proteins from kidneys of two-kidney, one-clip (2K1C) hypertensive Wistar rats. The experiment was repeated with 14-day ANGII infusion using Alzet osmotic mini pumps. with or without ANGII receptor AT1a inhibition using losartan in the drinking water. Mean arterial pressure increased after 2K1C or ANGII infusion and was inhibited with losartan. Heparin affinity chromatography and mass spectrometry were used to identify Annexin-A2 (ANXA2) as having differential nucleic acid-binding activity. Total Annexin-A2 protein expression was unchanged, whereas nucleic acid-binding activity was increased in both kidneys of 2K1C and after ANGII infusion through AT1a stimulation. Costaining of Annexin-A2 with alpha-smooth muscle actin and aquaporin 2 showed prominent expression in the endothelia of larger arteries and the cells of the inner medullary collecting duct. The nuclear factor of activated T cells (NFAT) transcription factor was identified as a likely Annexin-A2 target using enrichment analysis on a 2K1C microarray data set and identifying several binding sites in the regulatory region of the mRNA. Expression analysis showed that ANGII increases NFAT5 protein but not mRNA level and, thus, indicated that NFAT5 is regulated by posttranscriptional regulation, which correlates with activation of the RNA-binding protein Annexin-A2. In conclusion, we show that ANGII increases Annexin-A2 nucleic acid-binding activity that correlates with elevated protein levels of the NFAT5 transcription factor. NFAT signaling appears to be a major contributor to renal gene regulation in high-renin states.

  • 56.
    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.

  • 57.
    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.

  • 58.
    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)
  • 59.
    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)
  • 60. 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)
  • 61.
    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.
    Prevalence of subjective swallowing dysfunction in patients with stable COPD: Results from the TIE-study2017Conference paper (Other academic)
  • 62.
    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)
  • 63. 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.

  • 64. Granger, D. Neil
    et al.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Kvietys, Peter
    The Gastrointestinal Circulation: Physiology and Pathophysiology2015In: COMPREHENSIVE PHYSIOLOGY, ISSN 2040-4603, Vol. 5, no 3, p. 1541-1583Article in journal (Refereed)
    Abstract [en]

    The gastrointestinal (GI) circulation receives a large fraction of cardiac output and this increases following ingestion of a meal. While blood flow regulation is not the intense phenomenon noted in other vascular beds, the combined responses of blood flow, and capillary oxygen exchange help ensure a level of tissue oxygenation that is commensurate with organ metabolism and function. This is evidenced in the vascular responses of the stomach to increased acid production and in intestine during periods of enhanced nutrient absorption. Complimenting the metabolic vasoregulation is a strong myogenic response that contributes to basal vascular tone and to the responses elicited by changes in intravascular pressure. The GI circulation also contributes to a mucosal defense mechanism that protects against excessive damage to the epithelial lining following ingestion of toxins and/or noxious agents. Profound reductions in GI blood flow are evidenced in certain physiological (strenuous exercise) and pathological (hemorrhage) conditions, while some disease states (e.g., chronic portal hypertension) are associated with a hyperdynamic circulation. The sacrificial nature of GI blood flow is essential for ensuring adequate perfusion of vital organs during periods of whole body stress. The restoration of blood flow (reperfusion) to GI organs following ischemia elicits an exaggerated tissue injury response that reflects the potential of this organ system to generate reactive oxygen species and to mount an inflammatory response. Human and animal studies of inflammatory bowel disease have also revealed a contribution of the vasculature to the initiation and perpetuation of the tissue inflammation and associated injury response. (C) 2015 American Physiological Society.

  • 65.
    Grapensparr, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Auxiliary Cells for the Vascularization and Function of Endogenous and Transplanted Islets of Langerhans2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type 1 diabetes develops through the progressive destruction of the insulin-producing beta-cells. Regeneration or replacement of beta-cells is therefore needed to restore normal glucose homeostasis. Presently, normoglycemia can be achieved by the transplantation of whole pancreas or isolated islets of Langerhans. Islet transplantation can be performed through a simple laparoscopic procedure, but the long-term graft survival is low due to poor revascularization and early cell death.

    This thesis examined the possibility of using different auxiliary cells (Schwann cells, endothelial progenitor cells, and neural crest stem cells) to improve the engraftment and function of endogenous and transplanted islets.

    Co-transplantation of Schwann cells with islets improved islet graft function early after transplantation, and caused an increased islet mass at one month posttransplantation. However, the vascular densities of these grafts were decreased, which also related to an impaired graft function.

    Islet grafts containing endothelial progenitor cells had a superior vascular density, with functional chimeric blood vessels and substantially higher blood perfusion and oxygen tension than control transplants.

    By culturing and transplanting islets together with neural crest stem cells it was found that islets exposed to these cells had a higher beta-cell proliferation compared with control islets. At one month posttransplantation, the grafts with neural crest stem cells also had a superior vascular- and neural density.

    The potential of intracardially injected neural crest stem cells to home to the pancreas and ameliorate hyperglycemia in diabetic mice was investigated. During a three-week period after such cell treatment blood glucose concentrations decreased, but were not fully normalized. Neural crest stem cells were present in more than 10% of the pancreatic islets at two days postinjection, at which time the beta-cell proliferation was markedly increased when compared with islets of saline-treated diabetic animals. Three weeks later, a doubled beta-cell mass was observed in animals receiving neural crest stem cells.

    In summary, islets can easily be transplanted together with different auxiliary cells. Some of these cells provide the possibility of improving vascular- and neural engraftment, as well as beta-cell growth and survival. Systemic administration of neural crest stem cells holds the potential of regenerating the endogenous beta-cells.

    List of papers
    1. Influence of islet and peri-islet Schwann cells on vascularity and beta-cell function in endogenous and transplanted islets
    Open this publication in new window or tab >>Influence of islet and peri-islet Schwann cells on vascularity and beta-cell function in endogenous and transplanted islets
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-327312 (URN)
    Available from: 2017-08-09 Created: 2017-08-09 Last updated: 2017-08-09
    2. Bioengineering with Endothelial Progenitor Cells Improves the Vascular Engraftment of Transplanted Human Islets
    Open this publication in new window or tab >>Bioengineering with Endothelial Progenitor Cells Improves the Vascular Engraftment of Transplanted Human Islets
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-327311 (URN)
    Available from: 2017-08-09 Created: 2017-08-09 Last updated: 2017-08-09
    3. Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth
    Open this publication in new window or tab >>Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth
    Show others...
    2015 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 4, p. E583-E590Article in journal (Refereed) Published
    Abstract [en]

    Context: Neural crest stem cells (NCSCs) are capable of substantially improving murine islet function by promoting beta-cell proliferation. Objective: The present study aimed to investigate the potential of NCSCs to stimulate human beta-cell proliferation, and improve neural and vascular engraftment of human islets. Design, Setting, and Subjects: Human pancreatic islets from 18 brain-dead cadaveric donors (age range, 19-78 y) were obtained through the Nordic Network for Clinical Islet Transplantation. beta-cell proliferation and graft function was investigated at our experimental laboratory. Intervention and Main Outcome Measures: Human islets were transplanted, either alone or together with spheres of NCSCs. beta-cell proliferation, as well as islet neuralandvascular densities, were assessed by immunohistochemistry. Graft blood perfusion and oxygen tension were measured using laser-Doppler flowmetry and Clark microelectrodes, respectively. Results: Two days posttransplantation, the number of Ki67-positive beta-cells was doubled in human islets that had been exposed to NCSCs. Similar findings were obtained in vitro, as well as with EdU as proliferation marker. Four weeks posttransplantation, NCSC-exposed human islet grafts had much higher neural and vascular densities. The newly formed blood vessels were also functional, given that these human islets had a substantially higher blood perfusion and oxygen tension when compared with control transplants. Conclusion: We conclude that exposure to NCSCs stimulates human beta-cell proliferation, andthat these cells improve both the neural and vascular engraftment of transplanted human islets. NCSCs are a promising cellular therapy for translation into clinical use.

    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-253267 (URN)10.1210/jc.2014-4070 (DOI)000353361500009 ()25668197 (PubMedID)
    Available from: 2015-05-25 Created: 2015-05-25 Last updated: 2017-12-04Bibliographically approved
    4. Systemic neural crest stem cell treatment alleviates experimental type 1 diabetes by cellular homing to the damaged islets, inducing beta-cell regeneration
    Open this publication in new window or tab >>Systemic neural crest stem cell treatment alleviates experimental type 1 diabetes by cellular homing to the damaged islets, inducing beta-cell regeneration
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-327313 (URN)
    Available from: 2017-08-09 Created: 2017-08-09 Last updated: 2017-08-09
  • 66.
    Grapensparr, Liza
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Surface-Coating with Endothelial Progenitor Cells Improves Blood Flow, Oxygen Tension and Vascular Density in Experimentally Transplanted Human Pancreatic Islets2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S112-S112Article in journal (Other academic)
  • 67.
    Grapensparr, Liza
    et al.
    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 Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Vasylovska, Svitlana
    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 Neuroscience, Neuroanatomy.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The therapeutic role of endothelial progenitor cells in Type 1 diabetes mellitus2011In: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 6, no 5, p. 599-605Article, review/survey (Refereed)
    Abstract [en]

    Pancreatic beta-cells sense and adjust the blood glucose level by secretion of insulin. In Type 1 diabetes mellitus, these insulin-producing cells are destroyed, leaving the patients incapable of regulating blood glucose homeostasis. At the time of diagnosis, most patients still have 20-30% of their original beta-cell mass remaining. These residual beta-cells are targets for intervention therapies aimed at preventing further autoimmune destruction, in addition to increasing the number of existing beta-cells. Such a therapeutic option is highly desirable since it may lead to a full recovery of newly diagnosed patients, with no need for further treatment with immunosuppressant drugs or exogenous insulin administration. In this article, we propose that endothelial progenitor cells, a cell type known to promote and support neovascularization following endothelial injury, may be used as part of a combinational stem cell therapy aimed to improve the vascularization, survival and proliferation of beta-cells.

  • 68.
    Grapensparr, Liza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Zhanchun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Regenerative neurobiology.
    Carlsson, Per-Ola
    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 Medical Sciences, Transplantation and regenerative medicine.
    Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth2015In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 4, p. E583-E590Article in journal (Refereed)
    Abstract [en]

    Context: Neural crest stem cells (NCSCs) are capable of substantially improving murine islet function by promoting beta-cell proliferation. Objective: The present study aimed to investigate the potential of NCSCs to stimulate human beta-cell proliferation, and improve neural and vascular engraftment of human islets. Design, Setting, and Subjects: Human pancreatic islets from 18 brain-dead cadaveric donors (age range, 19-78 y) were obtained through the Nordic Network for Clinical Islet Transplantation. beta-cell proliferation and graft function was investigated at our experimental laboratory. Intervention and Main Outcome Measures: Human islets were transplanted, either alone or together with spheres of NCSCs. beta-cell proliferation, as well as islet neuralandvascular densities, were assessed by immunohistochemistry. Graft blood perfusion and oxygen tension were measured using laser-Doppler flowmetry and Clark microelectrodes, respectively. Results: Two days posttransplantation, the number of Ki67-positive beta-cells was doubled in human islets that had been exposed to NCSCs. Similar findings were obtained in vitro, as well as with EdU as proliferation marker. Four weeks posttransplantation, NCSC-exposed human islet grafts had much higher neural and vascular densities. The newly formed blood vessels were also functional, given that these human islets had a substantially higher blood perfusion and oxygen tension when compared with control transplants. Conclusion: We conclude that exposure to NCSCs stimulates human beta-cell proliferation, andthat these cells improve both the neural and vascular engraftment of transplanted human islets. NCSCs are a promising cellular therapy for translation into clinical use.

  • 69.
    Grapensparr, Liza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    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 Medical Sciences.
    Neural Crest Stem Cells Induce Beta-cell Proliferation in Cultured and Transplanted Human Pancreatic Islets2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S149-S149Article in journal (Other academic)
  • 70. Grubb, Tamara L
    et al.
    Högman, Marieann
    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 Medical Cell Biology, Integrativ Fysiologi.
    Edner, Anna
    Frendin, Jan H M
    Heinonen, Erkki
    Malavasi, Laís M
    Frostell, Claes G
    Ryden, Anneli
    Alving, Kjell
    Nyman, Görel C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Physiologic responses and plasma endothelin-1 concentrations associated with abrupt cessation of nitric oxide inhalation in isoflurane-anesthetized horses2008In: American Journal of Veterinary Research, ISSN 0002-9645, E-ISSN 1943-5681, Vol. 69, no 3, p. 423-430Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess physiologic responses and plasma endothelin (ET)-1 concentrations associated with abrupt cessation of nitric oxide (NO) inhalation in isoflurane-anesthetized horses. ANIMALS: 6 healthy adult Standardbreds. PROCEDURES: Horses were anesthetized with isoflurane in oxygen and placed in dorsal recumbency. Nitric oxide was pulsed into the respiratory tract for 2.5 hours, and then administration was abruptly discontinued. Just prior to commencement and at cessation of NO administration, and at intervals during a 30-minute period following cessation of NO inhalation, several variables including PaO(2), mean pulmonary artery pressure, venous admixture or pulmonary shunt fraction (Qs/Qt), and plasma ET-1 concentration were recorded or calculated. RESULTS: After cessation of NO inhalation, PaO(2) decreased slowly but significantly (172.7 +/- 29.8 mm Hg to 84.6 +/- 10.9 mm Hg) and Qs/Qt increased slowly but significantly (25 +/- 2% to 40 +/- 3%) over a 30-minute period. Mean pulmonary artery pressure increased slightly (14.0 +/- 1.3 mm Hg to 16.8 +/- 1 mm Hg) over the same time period. No change in serum ET-1 concentration was detected, and other variables did not change or underwent minor changes. CONCLUSIONS AND CLINICAL RELEVANCE: The improvement in arterial oxygenation during pulsed inhalation of NO to healthy isoflurane-anesthetized horses decreased only gradually during a 30-minute period following cessation of NO inhalation, and serum ET-1 concentration was not affected. Because a rapid rebound response did not develop, inhalation of NO might be clinically useful in the treatment of hypoxemia in healthy isoflurane-anesthetized horses.

  • 71.
    Göransson, Viktoria
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Johnsson, Cecilia
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Nylander, Olof
    Uppsala University, Department of Comparative Medicine. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
    Hansell, Peter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Renomedullary and intestinal hyaluronan content during body water excess: a study in rats and gerbils2002In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 542, no 1, p. 315-22Article in journal (Refereed)
    Abstract [en]

    Our previous studies in rats have suggested a role for renomedullary hyaluronan (HA) in water homeostasis. The gerbil is known for its unique ability to conserve water. In the present study renal papillary and intestinal HA were compared between groups of anaesthetized gerbils and rats before and after up to 6 h of I.V. water loading. Baseline papillary HA in gerbils was only 37 % of that in the rat. Water loading in rats increased the papillary HA content. Elevation was maximal (+27 %, P < 0.05) after 2 h of water loading and then declined to control levels after 6 h of water loading (+3 %, n.s.). In contrast, the gerbil responded with a decreased papillary HA content during water loading. The depression was maximal after 2 h (-49 %, P < 0.05) and was still 41 % below the control values after 6 h (P < 0.05). The urine flow rate increased rapidly in the rat and its maximum, 21 times above the control level (P < 0.05), occurred at the HA peak, i.e. after 2 h of water loading while in the gerbil, the urine flow rate increased slowly and slightly and was only six times above control values after 6 h of water loading (P < 0.05). The HA content along the intestine was similar in the two species: lowest in the duodenum and jejunum and highest in the distal colon. To conclude, in the rat, the elevation of papillary interstitial HA during acute water loading would counteract water reabsorption by changing the physico-chemical characteristics of the interstitial matrix favouring rapid water diuresis. This would work as a complement to the powerful regulation by ADH. The gerbil has a diametrically different regulation of papillary HA turnover during water loading. The decreased papillary HA level during water loading and the slow and small diuretic response may represent a genetic difference in adaptation to enhance the ability to conserve water in an arid environment.

  • 72.
    Göransson, Viktoria
    et al.
    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 Medical Cell Biology, Integrativ Fysiologi.
    Odlind, Cecilia
    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 Medical Cell Biology, Integrativ Fysiologi.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hansell, Peter
    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 Medical Cell Biology, Integrativ Fysiologi.
    Physiological role of hyaluronan in renal papillary water handling?1998In: Pflügers Archiv European Journal of Physiology, ISSN 0031-6768, Vol. 435, no Suppl, p. 211-Article, book review (Other academic)
  • 73.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Evaluation of methods for estimating renal medullary blood flow1992In: Ren Physiol Biochem, ISSN 1011-6524, Vol. 15, no 5, p. 217-30Article in journal (Refereed)
  • 74.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    In vivo evidence for a defect in the dopamine DA1 receptor in the prehypertensive Dahl salt-sensitive rat1995In: Experimental nephrology, ISSN 1018-7782, E-ISSN 1421-9956, Vol. 3, no 1, p. 15-22Article in journal (Refereed)
  • 75.
    Hansell, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Göransson, Viktoria
    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 Medical Cell Biology, Integrative Physiology.
    Maric, Christina
    Alcorn, Daine
    Gerdin, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hallgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hyaluronan in renal medullary water handling1999In: XVth International Congress of Nephrology, Buenos Aires, Argentina, 1999Conference paper (Other academic)
  • 76.
    Hansell, Peter
    et al.
    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 Medical Cell Biology, Integrative Physiology.
    Göransson, Viktoria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Odlind, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
    Maric, Christine
    Alcorn, Daine
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Gerdin, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    CD44 and hyaluronan in renal papillary water handling1999In: 32nd American Society of Nephrology (ASN) meeting, Miami Beach, Florida, USA, 1999Conference paper (Other academic)
  • 77.
    Hansell, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Källskog, Örjan
    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.
    Introduction to the Fourth Acta Physiologica Scandinavica International Symposium on vasodilators in the development of hypertension: NO and dopamine2000In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 168, no 1, p. 19-19Article in journal (Other academic)
  • 78.
    Hansell, Peter
    et al.
    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 Medical Cell Biology, Integrativ Fysiologi.
    Maric, C.
    Alcorn, D.
    Göransson, V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Johnsson, C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Renomedullary interstitial cells regulate hyaluronan turnover depending on growth media osmolality suggesting a arole in renal water handling1999In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 165, no 1, p. 115-116Article in journal (Refereed)
  • 79.
    Hansell, Peter
    et al.
    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.
    Stridh, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Renomedullary interstitial hyaluronan is important for hydration-induced diuresis2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26Article in journal (Other academic)
  • 80.
    Hansell, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Rügheimer, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Evi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Göransson, Viktoria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hyaluronan and renal ischemic damage2005Book (Refereed)
  • 81.
    Hansell, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Welch, William J.
    Blantz, Roland C.
    Palm, Fredrik
    Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension2013In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 40, no 2, p. 123-137Article, review/survey (Refereed)
    Abstract [en]

    The high renal oxygen (O2) demand is associated primarily with tubular O2 consumption (Qo2) necessary for solute reabsorption. Increasing O2 delivery relative to demand via increased blood flow results in augmented tubular electrolyte load following elevated glomerular filtration, which, in turn, increases metabolic demand. Consequently, elevated kidney metabolism results in decreased tissue oxygen tension. The metabolic efficiency for solute transport (Qo2/TNa) varies not only between different nephron sites, but also under different conditions of fluid homeostasis and disease. Contributing mechanisms include the presence of different Na+ transporters, different levels of oxidative stress and segmental tubular dysfunction. Sustained hyperglycaemia results in increased kidney Qo2, partly due to mitochondrial dysfunction and reduced electrolyte transport efficiency. This results in intrarenal tissue hypoxia because the increased Qo2 is not matched by a similar increase in O2 delivery. Hypertension leads to renal hypoxia, mediated by increased angiotensin receptor tonus and oxidative stress. Reduced uptake in the proximal tubule increases load to the thick ascending limb. There, the increased load is reabsorbed, but at greater O2 cost. The combination of hypertension, angiotensin II and oxidative stress initiates events leading to renal damage and reduced function. Tissue hypoxia is now recognized as a unifying pathway to chronic kidney disease. We have gained good knowledge about major changes in O2 metabolism occurring in diabetic and hypertensive kidneys. However, further efforts are needed to elucidate how these alterations can be prevented or reversed before translation into clinical practice.

  • 82. 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.

  • 83.
    Henriksnäs, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Atuma, Christer
    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.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Engstrand, Lars
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Acute effects of Helicobacter pylori extracts on gastric mucosal blood flow in the mouse2009In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 15, no 2, p. 219-225Article in journal (Refereed)
    Abstract [en]

    AIM: To investigate the mechanisms underlying the reduction in gastric blood flow induced by a luminal water extract of Helicobacter pylori (HPE).

    METHODS: The stomachs of isoflurane-anesthetized mice were exteriorized, and the mucosal surface exposed. Blood flow was measured with the laser-Doppler technique, and systemic arterial blood pressure monitored. C57BL/6 mice were exposed to water extract produced from H pylori strain 88-23. To investigate the role of a nerve- or iNOS-mediated pathway, we used intraluminal lidocaine and iNOS-/- mice. Blood flow response to the endogenous nitric oxide synthase inhibitor asymmetric dimethyl arginine (ADMA) was also assessed.

    RESULTS: In wild-type mice, HPE decreased mucosal blood flow by approximately 30%. This reduction was abolished in iNOS-deficient mice, and by pre-treatment with lidocaine. Luminally applied ADMA resulted in reduction in blood flow similar to that observed in wild-type mice exposed to HPE.

    CONCLUSION: A H pylori water extract reduces gastric mucosal blood flow acutely through iNOS- and nerve-mediated pathways.

  • 84.
    Holm, Lena
    et al.
    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.
    Assessment of mucus thickness and production in situ2012In: Methods in molecular biology, ISSN 1064-3745, Vol. 842, p. 217-227Article in journal (Refereed)
    Abstract [en]

    The nature of the mucus gel layer covering the gastrointestinal tract makes it difficult to study outside its natural site attached to the mucosa. Here, we describe a technique for intravital microscopy studies of the mucus gel layer from the stomach down to the colon in anesthetized rats and mice. Mucus thickness and accumulation rate in each segment of the gastrointestinal tract is measured with a micropipette technique under observation through a stereomicroscope. In this way, the nature of the mucus gel in vivo is readily studied, and effects of interventions or disease on the mucus can be determined in longitudinal studies or by comparing animals. Using this technique, we have been able to demonstrate that there are two forms of mucus gel adherent to the stomach and colon mucosa: one layer which is removable by suction and an underlying firm adherent gel layer, while in the small intestine, all mucus adhering to the mucosa can easily be removed.

  • 85.
    Holm, Lena
    et al.
    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.
    Perry, M A
    Department of Physiology and Pharmacology, University of New South Wales, Sydney, 2052, Australia.
    NO-flurbiprofen maintains duodenal blood flow, enhances mucus secretion contributing to lower mucosal injury2002In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 283, no 5, p. G1090-G1097Article in journal (Refereed)
    Abstract [en]

    This study investigates possible mechanisms behind the reduced gastrointestinal ulcerogenicity of nitric oxide (NO)-flurbiprofen compared with flurbiprofen. The duodenal mucosa of Inactin-anaesthetised rats was exteriorized for intravital microscopy. Blood flow was measured with laser-Doppler flowmetry (LDF), mucus thickness with micropipettes, ICAM-1 and P-selectin expression with dual-labeled antibody technique, and mucosal integrity by (51)Cr-EDTA permeability. Exposure of the duodenum to flurbiprofen (1.0 mg/ml) for 90 min significantly reduced LDF to 70 +/- 4%, whereas NO-flurbiprofen (1.3 mg/ml) had no significant effect. Mucus accumulation after 60-min exposure was 75 +/- 23 microm (control), -1 +/- 17 microm (flurbiprofen), and 104 +/- 35 microm (NO-flurbiprofen). Mucosal permeability to (51)Cr-EDTA was unchanged in the control and NO-flurbiprofen groups but increased significantly from 1.0 +/- 0.2 to 3.7 +/- 0.7 microl x min(-1) x g(-1) after 90-min exposure to flurbiprofen. Expression of ICAM-1 was significantly increased after oral flurbiprofen but not by NO-flurbiprofen. Positive effects of NO-flurbiprofen compared with flurbiprofen on mucus formation, blood flow, and adhesion molecule expression likely contribute to the reduced mucosal injury observed with NO-flurbiprofen.

  • 86.
    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.

  • 87.
    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.

  • 88.
    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)
  • 89.
    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)
  • 90.
    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)
  • 91.
    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)
  • 92.
    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.

  • 93.
    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.

  • 94.
    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.

  • 95. Jadert, Cecilia
    et al.
    Petersson, Joel
    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.
    Borniquel, Sara
    Holm, Lena
    Lundberg, Jon O.
    Physiological recycling of endogenous nitrate by oral bacteria regulates gastric mucus release2013In: Nitric oxide, ISSN 1089-8603, E-ISSN 1089-8611, Vol. 31, no S1, p. S22-S22Article in journal (Other academic)
  • 96.
    Jansson, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    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 Medical Sciences.
    Bodin, Birgitta
    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, Integrativ Fysiologi.
    Flow distribution during infusion of UW and HTK solution in anaesthetised rats2011In: Langenbeck's archives of surgery (Print), ISSN 1435-2443, E-ISSN 1435-2451, Vol. 396, no 5, p. 677-683Article in journal (Refereed)
    Abstract [en]

    Organ transplantation necessitates the use of preservation solutions to maintain the integrity of the organs during retrieval. The aim of this study was to investigate the flow distribution in abdominal organs in rats during acute infusion of preservation solution. Microspheres were used to estimate the distribution of flow in the pancreas, duodenum, ileum, colon, liver, kidneys and lungs in untreated Wistar-Furth rats and in animals with an opened abdominal cavity and catheterised aorta. Some animals were infused by free flow of 5 ml of UW, HTK or Ringer solution containing microspheres at a pressure of 100 cm H2O through an intra-aortic catheter. Opening of the abdominal cavity did not affect any of the organ blood flow values. However, the fraction of total pancreatic blood flow diverted through the islets increased. During infusion of microsphere-containing UW, HTK or Ringer solution, splanchnic and renal organ flow values, represented by microsphere contents, were similar. The fraction of microspheres found in the islets was lower in UW-infused rats. The number of microspheres present in the lungs or liver was very low, suggesting that shunting was negligible. Infusion of HTK and UW solution into anaesthetised rats results in a flow distribution which is similar to that in normal animals in most abdominal organs, but there is a reduction in islet blood perfusion by UW but not HTK solution.

  • 97. Johansson, Malin E. V.
    et al.
    Gustafsson, Jenny K.
    Sjöberg, Karolina E.
    Petersson, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Sjövall, Henrik
    Hansson, Gunnar C.
    Bacteria Penetrate the Inner Mucus Layer before Inflammation in the Dextran Sulfate Colitis Model2010In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 8, p. e12238-Article in journal (Refereed)
    Abstract [en]

    Background: Protection of the large intestine with its enormous amount of commensal bacteria is a challenge that became easier to understand when we recently could describe that colon has an inner attached mucus layer devoid of bacteria (Johansson et al. (2008) Proc. Natl. Acad. Sci. USA 105, 15064-15069). The bacteria are thus kept at a distance from the epithelial cells and lack of this layer, as in Muc2-null mice, allow bacteria to contact the epithelium. This causes colitis and later on colon cancer, similar to the human disease Ulcerative Colitis, a disease that still lacks a pathogenetic explanation. Dextran Sulfate (DSS) in the drinking water is the most widely used animal model for experimental colitis. In this model, the inflammation is observed after 3-5 days, but early events explaining why DSS causes this has not been described. Principal Findings: When mucus formed on top of colon explant cultures were exposed to 3% DSS, the thickness of the inner mucus layer decreased and became permeable to 2 mm fluorescent beads after 15 min. Both DSS and Dextran readily penetrated the mucus, but Dextran had no effect on thickness or permeability. When DSS was given in the drinking water to mice and the colon was stained for bacteria and the Muc2 mucin, bacteria were shown to penetrate the inner mucus layer and reach the epithelial cells already within 12 hours, long before any infiltration of inflammatory cells. Conclusion: DSS thus causes quick alterations in the inner colon mucus layer that makes it permeable to bacteria. The bacteria that reach the epithelial cells probably trigger an inflammatory reaction. These observations suggest that altered properties or lack of the inner colon mucus layer may be an initial event in the development of colitis.

  • 98. Johansson, Malin E V
    et al.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Petersson, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Velcich, Anna
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hansson, Gunnar C
    The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 39, p. 15064-15069Article in journal (Refereed)
    Abstract [en]

    We normally live in symbiosis with approximately 10(13) bacteria present in the colon. Among the several mechanisms maintaining the bacteria/host balance, there is limited understanding of the structure, function, and properties of intestinal mucus. We now demonstrate that the mouse colonic mucus consists of two layers extending 150 mum above the epithelial cells. Proteomics revealed that both of these layers have similar protein composition, with the large gel-forming mucin Muc2 as the major structural component. The inner layer is densely packed, firmly attached to the epithelium, and devoid of bacteria. In contrast, the outer layer is movable, has an expanded volume due to proteolytic cleavages of the Muc2 mucin, and is colonized by bacteria. Muc2(-/-) mice have bacteria in direct contact with the epithelial cells and far down in the crypts, explaining the inflammation and cancer development observed in these animals. These findings show that the Muc2 mucin can build a mucus barrier that separates bacteria from the colon epithelia and suggest that defects in this mucus can cause colon inflammation.

  • 99. Johansson, Mia
    et al.
    Synnerstad, Ingrid
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Acid transport through channels in the mucous layer of rat stomach2000In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 119, no 5, p. 1297-1304Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: We have reported previously that secreted acid moves through the mucous layer in restricted areas above the gastric crypts. The aim of this study was to visualize and study the dynamics of this event.

    METHODS: Anesthetized rats prepared for intravital microscopy of the gastric mucosa were divided in the following groups with respect to acid secretion: spontaneous; stimulated (pentagastrin, 40 microg. kg(-1). h(-1)); transiently inhibited (omeprazole, 400 micromol. kg(-1) for 7 days); and totally inhibited (omeprazole, 3 x 200 micromol. kg(-1) for 7 days). The mucus was stained with Congo red (blue, pH < 3; red, pH > 5.2), and photographs were taken through a stereomicroscope.

    RESULTS: During acid secretion, blue-colored crypt openings with attached thread-like (5-7 microm wide) structures (designated channels) were seen passing from the crypt openings through the mucus to the lumen. Red-colored channels and crypt openings were observed when acid secretion was transiently inhibited. Red-colored crypt openings but no channels were found after total inhibition of acid secretion for a week.

    CONCLUSIONS: The results suggest that secreted acid is transported through channels within the mucus. These channels are probably created by the high intraglandular pressure pushing acid and glandular mucus into the gel.

  • 100.
    Juul, Troels
    et al.
    Aarhus Univ, Dept Clin Med, MR Res Ctr, Aarhus, Denmark.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nielsen, Per Mose
    Aarhus Univ, Dept Clin Med, MR Res Ctr, Aarhus, Denmark.
    Bertelsen, Lotte Bonde
    Aarhus Univ, Dept Clin Med, MR Res Ctr, Aarhus, Denmark.
    Laustsen, Christoffer
    Aarhus Univ, Dept Clin Med, MR Res Ctr, Aarhus, Denmark.
    Ex vivo hyperpolarized MR spectroscopy on isolated renal tubular cells: A novel technique for cell energy phenotyping.2017In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 78, no 2, p. 457-461Article in journal (Refereed)
    Abstract [en]

    PURPOSE: It has been demonstrated that hyperpolarized (13) C MR is a useful tool to study cultured cells. However, cells in culture can alter phenotype, which raises concerns regarding the in vivo significance of such findings. Here we investigate if metabolic phenotyping using hyperpolarized (13) C MR is suitable for cells isolated from kidney tissue, without prior cell culture.

    METHODS: Isolation of tubular cells from freshly excised kidney tissue and treatment with either ouabain or antimycin A was investigated with hyperpolarized MR spectroscopy on a 9.4 Tesla preclinical imaging system.

    RESULTS: Isolation of tubular cells from less than 2 g of kidney tissue generally resulted in more than 10 million live tubular cells. This amount of cells was enough to yield robust signals from the conversion of (13) C-pyruvate to lactate, bicarbonate and alanine, demonstrating that metabolic flux by means of both anaerobic and aerobic pathways can be quantified using this technique.

    CONCLUSION: Ex vivo metabolic phenotyping using hyperpolarized (13) C MR in a preclinical system is a useful technique to study energy metabolism in freshly isolated renal tubular cells. This technique has the potential to advance our understanding of both normal cell physiology as well as pathological processes contributing to kidney disease.

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