Epalrestat is an inhibitor of aldose reductase in the polyol pathway and is used for the management of diabetic neuropathy clinically. Our pilot experiments and accumulated evidences showed that epalrestat inhibited polyol pathway and reduced sorbitol production, and suggested the potential renal protection effects of epalrestat on diabetic nephropathy (DN). To evaluate the protective effect of epalrestat, the db/db mice were used and exposed to epalrestat for 8 weeks, both the physiopathological condition and function of kidney were examined. For the first time, we showed that epalrestat markedly reduced albuminuria and alleviated the podocyte foot process fusion and interstitial fibrosis of db/db mice. Metabolomics was employed, and metabolites in the plasma, renal cortex, and urine were profiled using a gas chromatography-mass spectrometry (GC/MS)-based metabolomic platform. We observed an elevation of sorbitol and fructose, and a decrease of myo-inositol in the renal cortex of db/db mice. Epalrestat reversed the renal accumulation of the polyol pathway metabolites of sorbitol and fructose, and increased myo-inositol level. Moreover, the upregulation of aldose reductase, fibronectin, collagen III, and TGF-β1 in renal cortex of db/db mice was downregulated by epalrestat. The data suggested that epalrestat has protective effects on DN, and the inhibition of aldose reductase and the modulation of polyol pathway in nephritic cells be a potentially therapeutic strategy for DN.

中文翻译：

---

醛糖还原酶抑制剂依帕司他通过代谢调节对db / db小鼠糖尿病性肾病具有肾脏保护作用。

Epalrestat是多元醇途径中醛糖还原酶的抑制剂，在临床上用于治疗糖尿病性神经病。我们的先导实验和积累的证据表明，依帕司他可抑制多元醇途径并降低山梨醇的产生，并提示依帕司他对糖尿病性肾病（DN）有潜在的肾脏保护作用。为了评估依帕司他的保护作用，使用db / db小鼠并暴露于依帕司他8周，检查肾脏的生理病理状况和功能。首次，我们显示依帕司他显着降低白蛋白尿并减轻足细胞足突融合和db / db小鼠间质纤维化。使用了代谢组学，血浆，肾皮质，使用基于气相色谱-质谱（GC / MS）的代谢组学平台对尿液和尿液进行分析。我们观察到在db / db小鼠的肾皮质中山梨糖醇和果糖升高，肌醇减少。Epalrestat逆转了山梨糖醇和果糖的多元醇途径代谢产物的肾脏积累，并增加了肌醇水平。此外，依帕瑞司他下调了db / db小鼠肾皮质醛糖还原酶，纤连蛋白，胶原蛋白III和TGF-β1的表达。数据表明，依帕司他对DN具有保护作用，抑制醛糖还原酶和调节肾细胞中多元醇途径是DN的潜在治疗策略。db / db小鼠肾皮质中肌醇的减少。Epalrestat逆转了山梨糖醇和果糖的多元醇途径代谢产物的肾脏积累，并增加了肌醇水平。此外，依帕瑞司他下调了db / db小鼠肾皮质醛糖还原酶，纤连蛋白，胶原蛋白III和TGF-β1的表达。数据表明，依帕司他对DN具有保护作用，抑制醛糖还原酶和调节肾细胞中多元醇途径是DN的潜在治疗策略。db / db小鼠肾皮质中肌醇的减少。Epalrestat逆转了山梨糖醇和果糖的多元醇途径代谢产物的肾脏积累，并增加了肌醇水平。此外，依帕瑞司他下调了db / db小鼠肾皮质醛糖还原酶，纤连蛋白，胶原蛋白III和TGF-β1的表达。数据表明，依帕司他对DN具有保护作用，抑制醛糖还原酶和调节肾细胞中多元醇途径是DN的潜在治疗策略。