Macrophages play a critical role in the progression of clinical and experimental glomerular injury. Serum-stimulated human fetal mesangial cells in culture produce a chemotactic factor that is monocyte-selective. This chemotactic factor is most likely monocyte chemoattractant protein-1 (MCP-1) as a monoclonal antibody directed against MCP-1, but not an irrelevant antibody, suppressed the mesangial cell-derived chemotactic activity. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by lovastatin resulted in a reduction of the mesangial cell-derived chemotactic activity as well as MCP-1 mRNA expression. The inhibitory effects of lovastatin in the presence of exogenous cholesterol 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 additional mechanism by which HMG-CoA reductase inhibition in vivo may reduce glomerular injury.
Bibliographical noteFunding Information:
Guijarro) from the National Kidney Foundation of the Upper Midwest, and grants from the Baxter Healthcare Corporation, the American Heart Association, and Fondo de Investigacion Sanitaria (Nr.92/5510, 93/5439), Spanish Ministry of Health (C. Guijarro). The authors express their gratitude to Paul Walker, Frank Daniels, and Linda Schuveiller for their technical assistance and to Ellen Davis and Diane Erickson for their help in the preparation of this manuscript. We are also grateful to Dr. Ziad A. Massy for carefully reading the manuscript.