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 the isoprenylation of Rho
proteins. 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 actin cytoskeleton and of the expression of CTGF
mRNA. Incubation of the cells with
simvastatin or
lovastatin time-dependently and reversibly changed cell morphology and the actin cytoskeleton with maximal effects observed after about 18 h. Within the same time period,
statins reduced the basal expression of CTGF and interfered with CTGF induction by
lysophosphatidic acid (LPA) or
transforming growth factor beta.
Simvastatin and
lovastatin proved to be much more potent than
pravastatin (IC(50) 1 - 3 microM compared to 500 microM). The inhibition of CTGF expression was prevented when the cells were incubated with
mevalonate or geranylgeranylpyrophosphate (GGPP) but not by
farnesylpyrophosphate (FPP). Specific inhibition of
geranylgeranyltransferase-I by GTI-286 inhibited LPA-mediated CTGF expression whereas an inhibitor of farnesyltransferases
FTI-276 was ineffective.
Simvastatin reduced the binding of the
small GTPase RhoA to cellular membranes. The effect was prevented by
mevalonate and GGPP, but not FPP. These data are in agreement with the hypothesis that interference of
statins 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. The direct interference of
statins with the synthesis of CTGF, a
protein functionally related to the development of
fibrosis, may thus be a novel mechanism underlying the beneficial effects of
statins observed in renal diseases.