HUMAN MESANGIAL CELL PRODUCTION OF MONOCYTE CHEMOATTRACTANT PROTEIN-1- MODULATION BY LOVASTATIN

Macrophages play a critical role in the progression of clinical and ex perimental glomerular injury. Serum-stimulated human fetal mesangial c ells in culture produce a chemotactic factor that is monocyte-selectiv e. This chemotactic factor is most likely monocyte chemoattractant pro tein-1 (MCP-1) as a monoclonal antibody directed against MCP-1, but no t an irrelevant antibody, suppressed the mesangial cell-derived chemot actic activity. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (H MG-CoA) reductase by lovastatin resulted in a reduction of the mesangi al cell-derived chemotactic activity as well as MCP-1 mRNA expression. The inhibitory effects of lovastatin in the presence of exogenous cho lesterol were reversed by mevalonate, suggesting a role for isoprenoid intermediates of the mevalonate pathway and/or isoprenylated proteins in mesangial cell MCP-1 regulation. These findings suggest an additio nal mechanism by which HMG-CoA reductase inhibition in vivo may reduce glomerular injury.