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The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation
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The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation
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Journal Article
The aldose reductase inhibitor epalrestat exerts nephritic protection on diabetic nephropathy in db/db mice through metabolic modulation
2019
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Aldehyde Reductase - antagonists & inhibitors
/ Animals
/ Biomedical and Life Sciences
/ Diabetes
/ Diabetic Nephropathies - prevention & control
/ Enzyme Inhibitors - therapeutic use
/ Fibrosis
/ Fructose
/ Glucose
/ Inositol
/ Male
/ Mice
/ Protective Agents - therapeutic use
/ Rhodanine - analogs & derivatives
/ Rodents
/ Sorbitol
/ Thiazolidines - therapeutic use
/ Transforming growth factor-b1
/ Urine
/ Vaccine
