Contribution of Endogenous Inhibitor of Nitric Oxide Synthase to Hepatic Mitochondrial Dysfunction in Streptozotocin-induced Diabetic Rats

Abstract

Aims: Mitochondrial dysfunction plays important roles in the development of diabetes. Elevated nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) has been shown to be closely related to diabetes. But the relationship between them in diabetes has not been determined. This study was to explore the role of ADMA in hepatic mitochondrial dysfunction and its potential mechanisms in diabetic rats and hepatocytes. Methods: Respiratory enzymes activities, mitochondrial transmembrane potential and ATP content were measured to evaluate mitochondrial function. The copy number ratio of mitochondrial gene to nuclear gene was used to represent mitochondrial biogenesis. The activity of superoxide dismutase and malondialdehyde content were detected to reflect oxidative stress. Furthermore, changes in ADMA and NO contents, uncoupling protein 2 (UCP2) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) transcriptions were determined. Results: Elevated ADMA levels in serum of diabetic rats were found to be associated with hepatic mitochondrial dysfunction reflected by reductions of respiratory enzyme activities, mitochondrial membrane potential and ATP contents. Similar mitochondrial dysfunction also occurred in ADMA-treated hepatocytes. The mitochondrial dysfunction observed in diabetic rats or hepatocytes was accompanied with suppressions of mitochondrial biogenesis, PGC-1α transcription and NO synthesis as well as enhances of UCP 2 transcription and oxidative stress. These effects of ADMA could be attenuated by treatments with antioxidant or NO donor. Conclusions: These results indicate that elevated endogenous ADMA contributes to hepatic mitochondrial dysfunction in diabetic rats, and underlying mechanisms may be related to the suppression of mitochondrial biogenesis and mitochondrial uncoupling via inhibiting NO synthesis and enhancing oxidative stress.