Effect of inhibition of cholesterol synthetic pathway on the activation ofRas and MAP kinase in mesangial cells

Intermediary metabolites of cholesterol synthetic pathway are involved in c ell proliferation. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl c oenzyme A reductase, blocks mevalonate synthesis, and has been shown to inh ibit mesangial cell proliferation associated with diverse glomerular diseas es. Since inhibition of farnesylation and plasma membrane anchorage of the Ras proteins is one suggested mechanism by which lovastatin prevents cellul ar proliferation, we investigated the effect of lovastatin and key mevalona te metabolites on the activation of mitogen-activated protein kinase (MAP k inase) and Ras in murine glomerular mesangial cells. The preincubation of m esangial cells with lovastatin inhibited the activation of MAP kinase stimu lated by either FBS, PDGF, or EGF. Mevalonic acid and farnesylpyrophosphate , but not cholesterol or LDL, significantly prevented lovastatin-induced in hibition of agonist-stimulated MAP kinase. Lovastatin inhibited agonist-ind uced activation of Ras, and mevalonic acid and farnesylpyrophosphate antago nized this effect. Parallel to the MAP kinase and Ras data, lovastatin supp ressed cell growth stimulated by serum, and mevalonic acid and farnesylpyro phosphate prevented lovastatin-mediated inhibition of cellular growth. Thes e results suggest that lovastatin, by inhibiting the synthesis of farnesol, a key isoprenoid metabolite of mevalonate, modulates Ras-mediated cell sig naling events associated with mesangial cell proliferation. (C) 1999 Elsevi er Science B.V. All rights reserved.