The mevalonate pathway: Importance in mesangial cell biology and glomerular disease

Products of intracellular mevalonate metabolism are critical for the growth and proliferation of eukaryotic cells. These products include cholesterol and several nonsterol isoprenoids. The isoprenoid farnesyl is a particularly important intermediate in the mevalonate pathway. Farnesyl can be used to synthesize cholesterol and can also bind covalently to several low molecular mass GTP-binding proteins such as p21 ras. Farnesylated p21 ras may be critical for mitogenic signalling stimulated by growth factors such as platelet-derived growth factor. Inhibitors of the enzyme 3-hydroxy-3- methyglutaryl coenzyme A reductase, such as lovastatin and compactin, block the production of mevalonate and its metabolites. These agents have been shown to inhibit proliferation of many cell types. Recently we demonstrated that lovastatin inhibited proliferation of cultured glomerular mesangial cells. Lovastatin inhibition was overcome by the simultaneous addition of either mevalonate or farnesol, but not by exogenous low density lipoprotein cholesterol. These results suggested that farnesyl is critical for mesangial cell proliferation. In several experimental models of renal disease, chronic lovastatin administration reduced the extent of glomerular injury. The beneficial effects of lovastatin have been attributed to lowering of circulating lipid and lipoprotein levels. In view of recent data, however, it is possible that lovastatin may act to reduce glomerular injury, at least in part, through a direct action on mesangial cell proliferation.