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.

Mitochondrial fusion/fission process involved in the improvement of catalpol on high glucose-induced hepatic mitochondrial dysfunction

“…Our data showed decreased liver mitochondrial ATP content in HFD/STZ-diabetic mice, which is consistent with what has been previously reported in STZ-diabetic rats [25]. Catalpol administration can inhibit this decrease in a dosedependent manner (Fig.…”

“…However, investigations of mitochondrial dysfunction in diabetes mellitus were primarily focused on skeletal muscle and fat tissues, whereas few studies are focused in the liver [25]. In fact, hepatic mitochondrial dysfunction is closely related to the abnormal metabolism of glucose and lipids in diabetes, and it may be the underlying cause of hepatic insulin Data were expressed as the mean ± SEM from three independent experiments.…”

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

“…Furthermore, amino-thiol cysteamine generation due pantetheinase VNN-1 activity is associated with reduced γ-glutamylcysteine synthetase activity in the liver, which leads to less stored GSH [187]. In hepatocytes, increased asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, contributes to hepatic mitochondrial dysfunction in streptozotocininduced diabetic rats, accompanied by inhibitions of PGC-1α transcription, mitochondrial biogenesis, and NO synthesis and also by rising MDA levels [188]. Interestingly, these ADMA effects may be inhibited by treatments with an antioxidant like pyrrolidine dithiocarbamate [188].…”

“…In hepatocytes, increased asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, contributes to hepatic mitochondrial dysfunction in streptozotocininduced diabetic rats, accompanied by inhibitions of PGC-1α transcription, mitochondrial biogenesis, and NO synthesis and also by rising MDA levels [188]. Interestingly, these ADMA effects may be inhibited by treatments with an antioxidant like pyrrolidine dithiocarbamate [188]. In line with this, another report shows that the downregulation of GLUT2 and PGC-1α triggered by glucose oxidase is evidently inhibited by NAC in hepatocytes of rats [189].…”

“…The downregulation of PGC-1α expression in mice aggravates the harmful effects of either kainic acid on the hippocampus or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on substantia nigra [89]. In addition, pretreatment with PGC-1α antisense oligodeoxynucleotide reduces the expression of MnSOD and UCP-2, which leads to exacerbated oxidative injury and increased delayed neuronal death in the hippocampus after transient global ischemia [188]. Instead, enhanced PGC-1α expression may protect neural cells from oxidative stress-mediated cell death [89].…”