Simvastatin inhibits the cellular signaling and proliferative action of arginine vasopressin in cultured rat glomerular mesangial cells

Abstract

The present study was undertaken to determine whether an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, simvastatin, modulates the cellular action of arginine vasopressin (AVP) in the cultured rat glomerular mesangial cells. AVP increases cellular free calcium ([Ca2+]i) in a dose-dependent manner. The 1 x 10(-7) M AVP-mobilized [Ca2+]i was significantly reduced in the cells pretreated with 1 x 10(-6) M simvastatin. AVP produced a biphasic change in cellular pH, namely, an early acidification followed by a sustained alkalinization, and the AVP-induced cellular alkalinization disappeared after exposing to simvastatin. 1 x 10(-7) M AVP activated mitogen-activated protein (MAP) kinase from 15.5-30.4 pmol/mg protein, an effect significantly less in the presence of simvastatin. Also, 1 x 10(-7) M AVP significantly increased [3H]thymidine incorporation by 1.6-fold, and its incorporation was totally diminished in cells pretreated with simvastatin. The AVP-induced [Ca2+]i mobilization and MAP kinase activation were totally restored when cells were preexposed to a mixture of mevalonate and simvastatin. [3H]AVP receptor binding was not affected by the simvastatin treatment. 1 x 10(-7) AVP increased inositol trisphosphate production by 1.8-fold, which was significantly reduced by the presence of simvastatin. These results may indicate that nonsterol pathway plays a crucial role in the cellular action of AVP to produce cell growth of glomerular mesangium.