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, 40 (1), 86-97

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

Jun He et al. Acta Pharmacol Sin.

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.

Keywords: aldose reductase; diabetes; diabetic nephropathy; metabolomics; polyol pathway.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig. 1
Fig. 1
Biochemical assay of renal function and histological morphology data in different groups of mice. (a) Urinary albumin excretions, (b) creatinine clearance rate, (c) plasma creatinine levels, (d) plasma fasting glucose levels, (e) mesangial matrix fractions, (f) interstitial fibrosis area ratios, (g) glomerular basement membranes thickness, (h) foot process width, (i) glomerular tuft area. The data are expressed as the mean ± SD. *P < 0.05, ***P < 0.001 vs. WT group; #P < 0.05 vs. db/db group
Fig. 2
Fig. 2
Histological morphology and ultrastructural inspection of the nephric lesions of mice. ac PAS staining and df Masson’s trichrome staining, ×400 magnification; gi representative TEM images, ×1500 magnification and jl ×7000 magnification
Fig. 3
Fig. 3
Typical GC/MS chromatograms of the extracted molecules from the plasma, urine, and renal cortex of the mice. (a) Plasma, (b) urine, and (c) renal cortex. Typical compounds are identified and numbered as follows: 1. Lactate, 2. L-Alanine, 3. Oxalic acid, 4. 3-Hydroxybutyrate, 5. Valine, 6. Leucine, 7. Phosphate, 8. Proline, 9. Glycine, 10. Uracil, 11. Serine, 12. Threonine, 13. 3-Amino-isobutyrate, 14. Malate, 15. Hydroproline, 16. Creatinine, 17. Ornithine, 18. Taurine, 19. Glutamine, 20. Citrate, 21. Glucose, 22. Myo-inositol, 23. Oleic acid, 24. Arachidonic acid, 25. Cholesterol
Fig. 4
Fig. 4
Metabolic patterns of the three groups of mice based on multivariate statistical analysis of the GC/MS data. Score plots of the three groups and their PCA models for plasma data (a), urine data (b), renal cortex data (c); db/db vs. WT groups and their OPLS-DA models for plasma data (d), urine data (e), renal cortex data (f); epalrestat treatment vs. db/db groups and their OPLS-DA for plasma data (g), urine data (h), renal cortex data (i)
Fig. 5
Fig. 5
Heatmap visualizing the intensities of differential metabolites in the plasma (a), urine (b), and renal cortex extracts (c) of mice
Fig. 6
Fig. 6
The differential metabolites and associated metabolic pathways involved in db/db mice and the treatment with epalrestat in plasma (a), urine (b), and renal cortex extracts (c) of the mice
Fig. 7
Fig. 7
Relative abundance of myo-inositol, sorbitol, and fructose in the plasma, urine, and renal cortex of the mice. Myo-inositol (a–c), sorbitol (df), and fructose (gi) levels change in plasma, urine, and renal cortex extracts measured directly by GC/MS peak areas. The data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 vs. WT group; #P < 0.05, ##P < 0.01 vs. db/db group
Fig. 8
Fig. 8
Western blot analysis (a) of aldose reductase (b), fibronectin (c), TGF-β1 (d), nephrin (e), and podocin (f). The data are expressed as the mean ± SD. *P < 0.05 vs. WT group; #P < 0.05, ##P < 0.01 vs. db/db group
Fig. 9
Fig. 9
Representative immunohistochemical staining for collagen III (ac) and CTGF (df) in renal cortex, ×100 magnification, and quantitative analysis of relative AOD, (g) collagen III, and (h) CTGF. The data are expressed as the mean ± SD. **P < 0.01 vs. WT group; #P < 0.05 vs. db/db group

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