The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation  

作　　者：Jun He Hao-xue Gao Na Yang Xiao-dong Zhu Run-bin Sun Yuan Xie Cai-hong Zeng Jing-wei Zhang Jian-kun Wang Fei Ding Ji-ye Aa Guang-ji Wang 

机构地区：[1]Key Laboratory of Drug Metabolism and Pharmacokinetics,State Key Laboratory of Natural Medicines,China Pharmaceutical University,210009 Nanjing,China [2]Research Institute of Nephrology of PLA,Jinling Hospital,210002 Nanjing,China [3]Nanjing Hailing Pharmaceutical Co.Ltd.,Yangzi River Pharmaceutical Group,Co.Ltd.,210049 Nanjing,China

出　　处：《Acta Pharmacologica Sinica》2019年第1期86-97,共12页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of the People's Republic of China (81530098);the National Key Special Project of Science and Technology for Innovation Drugs of China (2017ZX09301013,2015ZX09501001);the Natural Science Foundation of Jiangsu Province (BL2014070);the project of university collaborative innovation center of Jiangsu province (Modern Chinese Medicine Center and Biological Medicine Center).

摘　　要：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 epalrestatmarkedlyreduced 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 ofaldose reductas and the modulation of polyol pathway in nephritic cells be a potentially therapeutic strategy for DN.

关 键 词：diabetes DIABETIC NEPHROPATHY POLYOL pathway metabolomics ALDOSE REDUCTASE 

分 类 号：R[医药卫生]