title: Activation of hypoxia-inducible factors prevents diabetic nephropathy.
abstract: 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, glomerular 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, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.
authors.affiliation: Division of Integrative Physiology, Department of Medical Cell Biology and.
authors.forename: Lina
authors.initials: L
authors.lastname: Nordquist
authors.affiliation: Division of Integrative Physiology, Department of Medical Cell Biology and.
authors.forename: Malou
authors.initials: M
authors.lastname: Friederich-Persson
authors.affiliation: Division of Integrative Physiology, Department of Medical Cell Biology and.
authors.forename: Angelica
authors.initials: A
authors.lastname: Fasching
authors.affiliation: Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden;
authors.forename: Per
authors.initials: P
authors.lastname: Liss
authors.affiliation: Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan; and.
authors.forename: Kumi
authors.initials: K
authors.lastname: Shoji
authors.affiliation: Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan; and.
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.affiliation: Division of Integrative Physiology, Department of Medical Cell Biology and.
authors.forename: Peter
authors.initials: P
authors.lastname: Hansell
authors.affiliation: Division of Integrative Physiology, Department of Medical Cell Biology and Division of Drug Research, Department of Medical and Health Sciences and Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden Fredrik.Palm@mcb.uu.se.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Palm
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000503:physiopathology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D051793:Hypoxia-Inducible Factor 1; D013113:Spin Labels; D003035:Cobalt; C018021:cobaltous chloride; C001803:tempol
keywords: diabetic nephropathy; hypoxia; proteinuria