EFFECTS OF LIPIDS ON THE PATHOGENESIS OF PROGRESSIVE RENAL-FAILURE - ROLE OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE INHIBITORS IN THE PREVENTION OF GLOMERULOSCLEROSIS

Increasing experimental evidence suggests that lipids might be importa nt modulators in progressive glomerulosclerosis. The inhibitors of 3-h ydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have demonstrat ed beneficial effects in different models of progressive renal failure . Monocyte infiltration, mesangial cell proliferation and mesangial ma trix expansion have been shown to be early events in the process of gl omerulosclerosis that can be lessened by HMG-CoA reductase inhibition. Recent experimental data suggest that these agents may also have glom erular protective effects independent of a reduction in circulating li pids. In vitro, lovastatin has been shown to downregulate mesangial ce ll production of monocyte chemoattractant protein-1 and colony-stimula ting factor, In addition, HMG-CoA reductase inhibitors can directly re duce mesangial cell proliferation. These effects appear related to the ability of this class of agents to inhibit mesangial cell formation o f intermediates of cholesterol formation, the nonsterol isoprenoids. A lthough low density lipoprotein cholesterol can induce mesangial cells to increase synthesis of matrix proteins, e.g., type-IV collagen, we have shown that lovastatin does not directly influence mesangial cell type-IV collagen metabolism, Thus, prevention of mesangial matrix expa nsion in vivo with type-IV collagen by HMG-CoA reductase inhibitors co uld be related to an indirect mechanism related to inhibition of monoc yte influx into the glomerulus. Alternatively, a direct effect of thes e agents, through their cholesterol-lowering capabilities, could play a role in reducing matrix expansion.