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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.