Rho-dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins)

1 It was supposed that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase (statins) might inhibit the expression of the fibrosis- related factor CTGF (connective tissue growth factor) by interfering with t he isoprenylation of Rho proteins. 2 The human renal fibroblast cell line TK173 was used as an in vitro model system to study the statin-mediated modulation of the structure of the acti n cytoskeleton and of the expression of CTGF mRNA. 3 Incubation of the cells with simvastatin or lovastatin time-dependently a nd reversibly changed cell morphology and the actin cytoskeleton with maxim al effects observed after about 18 h, 4 Within the same time period, statins reduced the basal expression of CTGF and interfered with CTGF induction by lysophosphatidic acid (LPA) or trans forming growth factor beta, Simvastatin and lovastatin proved to be much mo re potent than pravastatin (IC50 1 - 3 muM compared to 500 muM). 5 The inhibition of CTGF expression was prevented when the cells were incub ated with mevalonate or geranylgeranylpyrophosphate (GGPP) but not by farne sylpyrophosphate (FPP). Specific inhibition of geranylgeranyl transferase-1 by GTI-286 inhibited LPA-mediated CTGF expression whereas an inhibitor of farnesyltransferases FTI-276 was ineffective. 6 Simvastatin reduced the binding of the small GTPase RhoA to cellular memb ranes. The effect was prevented by mevalonate and GGPP, but not FPP. 7 These data are in agreement with the hypothesis that interference of stat ins with the expression of CTGF mRNA is primarily due to interference with the isoprenylation of RhoA, in line with previous studies, which have shown that RhoA is an essential mediator of CTGF induction. 8 The direct interference of statins with the synthesis of CTGF, a protein functionally related to the development of fibrosis, may thus be a novel me chanism underlying the beneficial effects of statins observed in renal dise ases.