NADPH‐oxidase and nNOS are responsible for the diabetes‐induced increase in transport‐dependent renal oxygen consumption

Abstract

Sustained hyperglycemia induces increased renal oxygen consumption resulting in reduced oxygen availability in the diabetic kidney. We tested the hypothesis that hyperglycemia‐induced over‐activation of NADPH‐oxidase and neuronal (n)NOS in the kidney is causing this elevated consumption. Oxygen consumption was measured in isolated proximal tubular (PT) cells from streptozotocin‐induced diabetic rats (n=7–9 per group) with and without treatment with apocynin (APO), a NADPH‐oxidase inhibitor, or SMTC, a selective nNOS inhibitor, or a combination of the two and the results were compared to normoglycemic controls (n=10). PT cells from untreated diabetic rats had increased total oxygen consumption compared to controls (40.6±7.9 vs. 10.9±2.0 nmol·mg protein−1·min−1). All treatments reduced the diabetes‐induced increase in oxygen consumption (APO 10.5±1.7, SMTC 19.7±3.0 and APO+SMTC 21.6±3.6 nmol·mg protein−1·min−1). The effects of APO and SMTC were linked to the transport‐related oxygen consumption since neither treatment had any significant effect on the oxygen consumption in cells pre‐incubated with ouabain. In conclusion, diabetes‐induced activation of NADPH‐oxidase and nNOS in PT cells results in increased oxygen consumption. The effects of APO and SMTC are not additive, suggesting a unifying pathway which warrants further studies.