Abstract
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-β1 (TGF-β1), 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-β1 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-β1 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.
Highlights
Emerging data have shown that the incidence and prevalence of nephrolithiasis are increasing remarkably [1]
The present study demonstrates the significant role of the Peroxisome proliferator-activated receptor- (PPAR-)γ-hepatocyte growth factor (HGF)/c-Met and Peroxisome proliferator-activated receptor-γ (PPAR-γ)-transforming growth factor-β1 (TGF-β1)/Smad pathways in both in vivo and in vitro calcium oxalate (CaOx) nephrolithiasis models
We suggest that oxalate inhibits PPAR-γ expression and activity via the TGF-β1-reactive oxygen species (ROS) pathway in renal tubular cells and that enhanced TGF-β1 expression is a result of PPAR-γ reduction
Summary
Emerging data have shown that the incidence and prevalence of nephrolithiasis are increasing remarkably [1]. 70% of human kidney stones are primarily composed of calcium oxalate (CaOx) [2]. Previous studies have shown that a high concentration of oxalate leads to renal tubular epithelial cell injury and contributes considerably to the deposition and progression of CaOx crystals [3]. A growing body of evidence suggests that increased CaOx crystal adhesion to and aggregation in renal tubular cells are associated with the overproduction of reactive oxygen species (ROS). ROS result in lipid peroxidation of the cellular membranes and serious renal tissue injuries, presumably through oxidative stress [5]. Antioxidant therapy can attenuate damage caused by renal oxidative stress and prevent
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