Simvastatin inhibits the cellular signaling and proliferative action of arginine vasopressin in cultured rat glomerular mesangial cells.
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.
Ishikawa
S
S
Department of Medicine, Jichi Medical School, Tochigi, Japan.
Kawasumi
M
M
Saito
T
T
D000818:Animals; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007700:Kinetics; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D015544:Inositol 1,4,5-Trisphosphate; D004247:DNA; D008148:Lovastatin; D019821:Simvastatin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013755:Tetradecanoylphorbol Acetate; D008798:Mevalonic Acid; D002118:Calcium; D013936:Thymidine