Fluvastatin inhibits the expression of fibronectin in human peritoneal mesothelial cells induced by high-glucose peritoneal dialysis solution via SGK1 pathway.

Abstract

Previous studies showed that statins may have protective effects on peritoneal mesothelial cells (PMC) cultured in high glucose. However, the mechanisms are not clear yet. Several studies demonstrated that serum- and glucocorticoid-inducible kinase 1 (SGK1) is implicated in tissue fibrosis of liver, lung and kidney by regulating the expression of many profibrogenic cytokines and extracellular matrix (e.g., fibronectin). However, few available reports elucidated whether the SGK1 is involved in the pathogenesis of peritoneal fibrosis (PF) in patients with peritoneal dialysis (PD). So far, there is no study about the interaction between the statins and SGK1 in PMC. The purpose of this study was to identify whether fluvastatin may decrease the expression of fibronectin (FN) in human peritoneal mesothelial cells (HPMC) cultured with high-glucose peritoneal dialysis solution (HGPDS) by affecting SGK1 signal pathway. Cultured HPMC were divided into groups of control, high-glucose peritoneal dialysis solution (HGPDS), HGPDS with fluvastatin (10(-8) mol/L ~ 10(-6) mol/L) or GSK650394 10(-5) mol/L (the competitive inhibitor of SGK1), fluvastatin 10(-6) mol/L or GSK650394 10(-5) mol/L alone. The expression of SGK1 and FN was detected by RT-PCR, western immunoblotting or ELISA. Compared with the control, the mRNA and protein expression of SGK1 and FN increased significantly in HPMC treated with HGPDS (p < 0.05). GSK650394 significantly decreased the upregulated mRNA and protein expression of SGK1 and FN induced by HGPDS (p < 0.05), and fluvastatin had the same effects as GSK650394 in a dose-dependent manner (p < 0.05). Expression of SGK1 and FN increased in HPMC induced by HGPDS. Treated with fluvastatin and the SGK1-inhibitor GSK650394, abnormalities of SGK1 and FN could be corrected partially, which suggested that the SGK1 pathway was implicated in the pathogenesis of PF, and that fluvastatin might decrease the expression of SGK1 so as to meliorate the progression of PF.