Abstract
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.
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Acknowledgements
We want to thank Dr. Xiao-dong Zhu for his help in technical support for transmission electron microscopy study in the Research Institute of Nephrology of PLA, Jinling Hospital, Nanjing, China. This study was financially supported by 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), and the project of university collaborative innovation center of Jiangsu province (Modern Chinese Medicine Center and Biological Medicine Center).
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JH, H-xG, NY, X-dZ, C-hZ, and J-kW performed the experiments; JH and R-bS analyzed the data; JH and J-yA interpreted the results of the experiment, prepared figures, and drafted the manuscript; YX, J-wZ, and FD helped to design the research; J-yA and G-jW revised the manuscript; G-jW approved the final version of the manuscript.
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He, J., Gao, Hx., Yang, N. et al. The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation. Acta Pharmacol Sin 40, 86–97 (2019). https://doi.org/10.1038/s41401-018-0043-5
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DOI: https://doi.org/10.1038/s41401-018-0043-5
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