Effects Of A Novel PPARγ Agonist On Cell Proliferation In ADPKD Cystic-lining Epithelial Cells

Objective: To investigate the cell localization ofβ-catenin in human ADPKD kidney tissues and PKDV/V mouse, and the effects of a novel PPAR-γagonist DH9 on the proliferation in human polycystic kidney cyst-lining epithelial cells. Methods: Distribution differences ofβ-catenin in ADPKD patients and PKDV/V mouse were examined by using immunohistochemical method. The cyst-lining epithelial cells(WT9-12)from human polycystic kidney were treated with DH9 or rosiglitazone for 24,48,72,96 hours with or without GW9662. The cell proliferation was assessed by MTT.Cell cycle and apoptosis were analyzed by flow cytometry.The phospho-β-catenin/totalβ-catenin, phospho-GSK3β/total GSK3, cyclinA, P21 CIP/WAF1, Bax, Bcl-2 were detected by Western blotting. Results: The protein level ofβ-catenin were significant enhanced not only in cytoplasm but also in nucleus of polycystic kidney cyst-lining epithelial cells. DH9 induced significant inhibition of cell growth, the efficiency of growth inhibition is more potent than rosiglitazone through PPAR-γindependent way. We found DH9 has no affected on the mRNA level ofβ-catenin, but can facilitateβ-catenin downregulation and phosphor-β-catenin upregulation in a dose-dependent and time-dependent manner. Inhibition of GSK3βby SB216763 could protest against DH9-facilitatedβ-catenin repression despite phosphorylating deactivation. The effects were also mediated by S cell cycle arrest through cyclinA downregulation and P21 CIP/WAF1 upregulation, apoptosis induction through decreasing Bcl-2/Bax. Conclusion: DH9 can effectively inhibit cell proliferation through PPARγindependent way. The effects may be mediated by S cell cycle arrest, Wnt/β-catenin pathway suppression and apoptosis induction.