Rosiglitazone Suppresses Calcium Oxalate Crystal Binding and Oxalate-Induced Oxidative Stress in Renal Epithelial Cells by Promoting PPAR- γ Activation and Subsequent Regulation of TGF- β 1 and HGF Expression.

Peroxisome proliferator-activated receptor- (PPAR-) γ is a ligand-dependent transcription factor, and it has become evident that PPAR- γ agonists have renoprotective effects, but their influence and mechanism during the development of calcium oxalate (CaOx) nephrolithiasis remain unknown. Rosiglitazone (RSG) was used as a representative PPAR- γ agonist in our experiments. The expression of transforming growth factor- β 1 (TGF- β 1), hepatocyte growth factor (HGF), c-Met, p-Met, PPAR- γ , p-PPAR- γ (Ser112), Smad2, Smad3, pSmad2/3, and Smad7 was examined in oxalate-treated Madin-Darby canine kidney (MDCK) cells and a stone-forming rat model. A CCK-8 assay was used to evaluate the effects of RSG on cell viability. In addition, intracellular reactive oxygen species (ROS) levels were monitored, and lipid peroxidation in renal tissue was detected according to superoxide dismutase and malondialdehyde levels. Moreover, the location and extent of CaOx crystal deposition were evaluated by Pizzolato staining. Our results showed that, both in vitro and in vivo , oxalate impaired PPAR- γ expression and phosphorylation, and then accumulative ROS production was observed, accompanied by enhanced TGF- β 1 and reduced HGF. These phenomena could be reversed by the addition of RSG. RSG also promoted cell viability and proliferation and decreased oxidative stress damage and CaOx crystal deposition. However, these protective effects of RSG were abrogated by the PPAR- γ -specific inhibitor GW9662. Our results revealed that the reduction of PPAR- γ activity played a critical role in oxalate-induced ROS damage and CaOx stone formation. RSG can regulate TGF- β 1 and HGF/c-Met through PPAR- γ to exert antioxidant effects against hyperoxaluria and alleviate crystal deposition. Therefore, PPAR- γ agonists may be expected to be a novel therapy for nephrolithiasis, and this effect is related to PPAR- γ -dependent suppression of oxidative stress.
Competing Interests: The authors declare that they have no competing interests.
(Copyright © 2019 Ya-Dong Liu et al.)