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首页> 外文期刊>Cellular Physiology and Biochemistry >Contribution of endogenous inhibitor of nitric oxide synthase to hepatic mitochondrial dysfunction in streptozotocin-induced diabetic rats
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Contribution of endogenous inhibitor of nitric oxide synthase to hepatic mitochondrial dysfunction in streptozotocin-induced diabetic rats

机译：内源性一氧化氮合酶抑制剂对链脲佐菌素诱导的糖尿病大鼠肝线粒体功能障碍的贡献

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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.
机译：目的：线粒体功能障碍在糖尿病的发展中起重要作用。一氧化氮（NO）合酶抑制剂不对称二甲基精氨酸（ADMA）升高已被证明与糖尿病密切相关。但他们之间在糖尿病中的关系尚未确定。本研究旨在探讨ADMA在糖尿病大鼠和肝细胞肝线粒体功能障碍中的作用及其潜在机制。方法：通过测定呼吸酶活性，线粒体跨膜电位和ATP含量来评估线粒体功能。线粒体基因与核基因的拷贝数比代表线粒体的生物发生。检测超氧化物歧化酶的活性和丙二醛含量以反映氧化应激。此外，测定了ADMA和NO含量，解偶联蛋白2（UCP2）和过氧化物酶体增殖物激活的受体-γ共激活因子1α（PGC-1α）转录的变化。结果：发现糖尿病大鼠血清中的ADMA水平升高与肝线粒体功能障碍有关，这可通过呼吸酶活性，线粒体膜电位和ATP含量的降低来反映。在ADMA处理的肝细胞中也发生了类似的线粒体功能障碍。在糖尿病大鼠或肝细胞中观察到的线粒体功能障碍伴随着线粒体生物发生，PGC-1α转录和NO合成的抑制，以及UCP 2转录和氧化应激的增强。 ADMA的这些作用可以通过抗氧化剂或NO供体的处理来减弱。结论：这些结果表明，内源性ADMA升高可导致糖尿病大鼠肝线粒体功能障碍，其潜在机制可能与通过抑制NO合成和增强氧化应激来抑制线粒体生物发生和线粒体解偶联有关。

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