Simvastatin reverses high glucose-induced apoptosis of mesangial cells via modulation of Wnt signaling pathway

Background/Aims: Disruption of Wnt/beta-catenin signaling in mesangial cells is a pathogenic consequence of diabetic nephropathy. We examined the role of simvastatin (SIM) in modulation of Wnt/beta-catenin signaling in the apoptosis of high glucose (HG)-stressed mesangial cells in vitro and in vivo. Methods: For in vitro studies, we cultured mesangial cells, with or without SIM pretreatment, in 35 m M glucose and then assayed Wnt activity and apoptosis. For in vivo studies, we administered SIM to streptozocin-induced diabetic rats for 28 days and then dissected renal tissues for immunohistological assessment of Wnt signal expression and apoptosis of glomerular cells. Results: SIM reduced the promotional effect of HG on caspase-3 expression, PARP activation, and cell apoptosis. HG significantly reduced Wnt4 and Wnt5a mRNA expression and SIM restored Wnt4 and Wnt5a mRNA expression to the level of controls. SIM also suppressed HG-mediated activation of GSK-3b and restored nuclear beta-catenin levels and phospho-Akt expression. This suggests that SIM alters the stability of beta-catenin, a critical element of mesangial cell survival. Exogenous SIM treatment blocked DNA fragmentation, increased the Wnt/beta-catenin immunoreactivities of cells adjacent to renal glomeruli, and attenuated urinary protein secretion in diabetic rats. Conclusions: SIM reduces the detrimental effects of HG on diabetic renal glomeruli in vitro and in vivo. SIM prevents HG-induced downregulation of Wnt/beta-catenin signaling and thereby blocks mesangial cell apoptosis. Copyright (C) 2007 S. Karger AG, Basel.