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Deletion of Uncoupling Protein‐2 reduces renal mitochondrial leak respiration, intrarenal hypoxia and proteinuria in a mouse model of type 1 diabetes
Author(s) -
FriederichPersson M.,
Persson P.,
Hansell P.,
Palm F.
Publication year - 2018
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.13058
Subject(s) - mitochondrion , endocrinology , medicine , hypoxia (environmental) , kidney , respiration , proteinuria , diabetes mellitus , biology , cellular respiration , renal function , oxidative phosphorylation , chemistry , oxygen , biochemistry , anatomy , organic chemistry
Aim Uncoupling protein‐2 ( UCP ‐2) can induce mitochondrial uncoupling in the diabetic kidney. Although mitochondrial uncoupling reduces oxidative stress originating from the mitochondria and can be regarded as a protective mechanism, the increased oxygen consumption occurring secondarily to increased mitochondria uncoupling, that is leak respiration, may contribute to kidney tissue hypoxia. Using UCP ‐2 −/− mice, we tested the hypothesis that UCP ‐2‐mediated leak respiration is important for the development of diabetes‐induced intrarenal hypoxia and proteinuria. Methods Kidney function, in vivo oxygen metabolism, urinary protein leakage and mitochondrial function were determined in wild‐type and UCP ‐2 −/− mice during normoglycaemia and 2 weeks after diabetes induction. Results Diabetic wild‐type mice displayed mitochondrial leak respiration, pronounced intrarenal hypoxia, proteinuria and increased urinary KIM ‐1 excretion. However, diabetic UCP ‐2 −/− mice did not develop increased mitochondrial leak respiration and presented with normal intrarenal oxygen levels, urinary protein and KIM ‐1 excretion. Conclusion Although functioning as an antioxidant system, mitochondria uncoupling is always in co‐occurrence with increased oxygen consumption, that is leak respiration; a potentially detrimental side effect as it can result in kidney tissue hypoxia; an acknowledged unifying pathway to nephropathy. Indeed, this study demonstrates a novel mechanism in which UCP ‐2‐mediated mitochondrial leak respiration is necessary for the development of diabetes‐induced intrarenal tissue hypoxia and proteinuria.