Effect of pravastatin on type IV collagen secretion and mesangial cell proliferation

Background. The mevalonate pathway is important for the biosynthesis of iso prenoids such as geranylgeranylpyrophosphate (GGPP) and farnesylpyrophospha te (FPP) as well as cholesterol. It has been reported that treatment with 3 -hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor ameliora tes glomerular injury in several experimental models of progressive glomeru lar disease. The present investigation was performed to elucidate the role of mevalonate metabolites in mesangial cell proliferation and extracellular matrix accumulation. Method. Cycling or quiescent human mesangial cells were incubated in RPMI16 40 containing 10% heat-inactivated fetal calf serum (FCS) in the absence or presence of pravastatin, an inhibitor of HMG-CoA reductase, and mevalonate metabolites. Type IV collagen secretion and mRNA expression, [H-3]thymidin e incorporation was measured. Cell cycle phases were monitored by flow cyto metry. Results. Pravastatin inhibited FCS-stimulated type IV collagen secretion (I C50 = 210 mu M) and mRNA expression. Pravastatin also inhibited FCS-stimula ted [H-3]-thymidine incorporation (IC50 = 430 mu M). Analysis with flow cyt ometry revealed that pravastatin inhibited G1 to S phase transition of FCS- stimulated mesangial cells. Mevalonate reversed these inhibitory effects of pravastatin completely. Among two major metabolites of mevalonate, GGPP an d FPP, only GGPP reversed pravastatin-induced inhibition of type IV collage n secretion, DNA synthesis and G1 to S phase progression. Conclusion. The present results suggest that GGPP plays a critical role in the type IV collagen secretion and G1 to S phase transition in FCS-stimulat ed human mesangial cells.