Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.
Kidney Int. 2010 May;77(10):861-9. doi: 10.1038/ki.2010.11. Epub 2010 Feb 17.
The antidiabetic drug metformin can diminish apoptosis induced by oxidative stress in endothelial cells and prevent vascular dysfunction even in nondiabetic patients. Here we tested whether it has a beneficial effect in a rat model of gentamicin toxicity. Mitochondrial analysis, respiration intensity, levels of reactive oxygen species, permeability transition, and cytochrome c release were assessed 3 and 6 days after gentamicin administration. Metformin treatment fully blocked gentamicin-mediated acute renal failure. This was accompanied by a lower activity of N-acetyl-beta-D-glucosaminidase, together with a decrease of lipid peroxidation and increase of antioxidant systems. Metformin also protected the kidney from histological damage 6 days after gentamicin administration. These in vivo markers of kidney dysfunction and their correction by metformin were complemented by in vitro studies of mitochondrial function. We found that gentamicin treatment depleted respiratory components (cytochrome c, NADH), probably due to the opening of mitochondrial transition pores. These injuries, partly mediated by a rise in reactive oxygen species from the electron transfer chain, were significantly decreased by metformin. Thus, our study suggests that pleiotropic effects of metformin can lessen gentamicin nephrotoxicity and improve mitochondrial homeostasis.
抗糖尿病药物二甲双胍可减少内皮细胞氧化应激诱导的细胞凋亡，并预防血管功能障碍，即使在非糖尿病患者中也是如此。在这里，我们测试了它在庆大霉素毒性大鼠模型中的有益效果。在庆大霉素给药后 3 天和 6 天评估了线粒体分析、呼吸强度、活性氧水平、通透性转换和细胞色素 c 释放。二甲双胍治疗完全阻断了庆大霉素介导的急性肾衰竭。这伴随着 N-乙酰-β-D-氨基葡萄糖苷酶活性降低，同时脂质过氧化减少和抗氧化系统增加。庆大霉素还可保护肾脏免受给药 6 天后的组织学损伤。这些体内肾功能障碍标志物及其被二甲双胍纠正的情况，通过体外线粒体功能研究得到了补充。我们发现，庆大霉素处理耗尽了呼吸成分（细胞色素 c、NADH），可能是由于线粒体过渡孔的开放。这些损伤部分是由电子传递链中活性氧的增加介导的，而二甲双胍可显著减少这些损伤。因此，我们的研究表明，二甲双胍的多效作用可以减轻庆大霉素的肾毒性并改善线粒体平衡。
