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.