title: Kidney hypoxia, attributable to increased oxygen consumption, induces nephropathy independently of hyperglycemia and oxidative stress.
abstract: Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. To date, it has been difficult to determine the role of kidney hypoxia, per se, for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg per day per kg bodyweight by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion, and histological findings were determined and compared with vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose, or markers of oxidative stress but increased kidney oxygen consumption, and reduced cortical and medullary concentrations of glucose and glycogen, and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression, and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia, per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Biomedical Center, Husargatan 3, SE-751 23, Uppsala, Sweden. Malou.Friederich@mcb.uu.se.
authors.forename: Malou
authors.initials: M
authors.lastname: Friederich-Persson
authors.forename: Erik
authors.initials: E
authors.lastname: Thörn
authors.forename: Peter
authors.initials: P
authors.lastname: Hansell
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.forename: Max
authors.initials: M
authors.lastname: Levin
authors.forename: Fredrik
authors.initials: F
authors.lastname: Palm
mesh_terms: D000818:Animals; D004140:Dinitrophenols / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology*; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000502:physiology; D014475:Uncoupling Agents / Q000494:pharmacology; D014746:Vimentin / Q000378:metabolism
chemical_list: D004140:Dinitrophenols; D014475:Uncoupling Agents; D014746:Vimentin; D006003:Glycogen; D005947:Glucose
keywords: cell hypoxia; chronic kidney disease; dinitrophenols; kidney; nephropathy, chronic tubulointerstitial; oxygen consumption; uncoupling agents
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