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Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy
Uppsala University, Sweden.
Uppsala University, Sweden.
Uppsala University, Sweden.
Uppsala University, Sweden.
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2015 (English)In: Journal of the American Society of Nephrology, ISSN 1046-6673, Vol. 26, no 2, 328-338 p.Article in journal (Refereed) Published
Abstract [en]

Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glonnerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetes-induced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharnnacologic activation of the HIF system may prevent development of diabetic nephropathy.

Place, publisher, year, edition, pages
American Society of Nephrology , 2015. Vol. 26, no 2, 328-338 p.
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-114575DOI: 10.1681/ASN.2013090990ISI: 000348623700012PubMedID: 25183809OAI: diva2:791461

Funding Agencies|Swedish Medical Research Council; Swedish Society for Medical Research; Swedish Heart-Lung Foundation; Swedish Diabetes Foundation; Japanese Society for Promotion of Science [24390213]

Available from: 2015-02-27 Created: 2015-02-26 Last updated: 2015-02-27

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Palm, Fredrik
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Division of Drug ResearchFaculty of Health SciencesCenter for Medical Image Science and Visualization (CMIV)
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