Lovastatin Reduces Glomerular Macrophage Influx and Expression of Monocyte Chemoattractant Protein-1 mRNA in Nephrotic Rats Y-S Park, MD, Carlos Guijarro, MD, PhD, Youngki Kim, MD, Ziad A. Massy, MD, Bertram L. Kasiske, MD, William F. Keane, MD, and Michael P. O’Donnell, PhD ● Glomerular expression of monocyte chemoattractant protein-1 (MCP-1) and subsequent glomerular macrophage infiltration may play an important role in the development of glomerulosclerosis. Previous studies have shown that lovastatin ameliorates experimental renal disease and reduces MCP-1 expression in serum-stimulated, cultured mesangial cells. We investigated the effects of lovastatin on glomerular MCP-1 expression and macrophage infiltration in rats with puromycin aminonucleoside (PA) nephrosis, an experimental model of renal disease characterized by early macrophage infiltration. Male Sprague-Dawley rats were pretreated for 5 days with either lovastatin (4 mg/kg) or vehicle. At the end of pretreatment, the lovastatin-pretreated rats received a single IV injection of PA (50 mg/kg) and continued to receive daily lovastatin thereafter. The vehicle-pretreated rats received IV injections of either PAor saline, and continued to receive daily vehicle treatment thereafter. Ten days after PA injection, the vehicle-treated PA rats showed increased (P F 0.05) serum cholesterol (359  25 mg/100 mL) and urine albumin excretion (343  95 mg/24 hr), compared with the vehicle-treated control rats (61  3 mg/100 mL and 2.5  0.6 mg/24 hr, respectively). Serum cholesterol (193  22 mg/dL) and urine albumin excretion (255  68 mg/24 hr) were less in the lovastatin-treated PA rats than in the vehicle-treated PA rats. The number of glomerular macrophages, assessed as ED-1–positive cells, per glomerular profile was increased 77% in the vehicle-treated PA rats (3.3  0.2) compared with the vehicle-treated control rats (1.8  0.2) (P F 0.05). By contrast, the number of glomerular macrophages was not elevated in the lovastatin-treated PA rats (2.3  0.2). Thus, lovastatin in vivo can attenuate glomerular macrophage infiltration. This may represent one mechanism by which lovastatin ameliorates experimental glomerular disease.  1998 by the National Kidney Foundation, Inc. INDEX WORDS: Glomerulosclerosis; albuminuria; cholesterol; puromycin; mesangium. G LOMERULAR infiltration of monocyte- derived macrophages may play an impor- tant role in the development of focal glomerulo- sclerosis. 1-6 One factor that appears to be important for migration of monocytes into the glomerular mesangium is monocyte chemoat- tractant protein-1 (MCP-1). MCP-1 may be produced by different glomerular cell types, and we and others have shown that MCP-1 is the primary monocyte chemoattractant produced by mesangial cells in vitro. 7-10 In several experimental models of progressive renal disease, inhibition of the enzyme 3-hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) re- ductase with the agent lovastatin has reduced albuminuria and the extent of glomerulosclero- sis. 11-15 Although the exact mechanism by which lovastatin ameliorates experimental renal injury is unknown, recent experimental studies have suggested that HMG-CoA reductase inhibitors may have direct effects on the glomerulus. 10,16,17 Importantly, we have shown in vitro that lova- statin inhibits serum-stimulated mesangial cell production of MCP-1. 10 Whether HMG-CoA reductase inhibitors exert a similar effect in vivo has not been reported. In the current study, we investigated the effects of lovastatin on glomerular MCP-1 expres- sion and macrophage infiltration in rats with puromycin aminonucleoside (PA) nephrosis. PA nephrosis is an experimental model of progres- sive glomerulosclerosis that is characterized by early glomerular macrophage accumulation. Har- ris et al 15 have previously reported that lovastatin reduces glomerular injury and preserves renal function in rats with PA nephrosis. We hypoth- esized that lovastatin might reduce glomerular MCP-1 expression and macrophage infiltration From the Department of Medicine, Division of Nephrol- ogy, Hennepin County Medical Center, and Department of Pediatrics, University of Minnesota Medical School, Minne- apolis, MN. Received July 28, 1997; accepted as submitted August 15, 1997. Supported in part by grants from the Baxter Extramural Grant Program, the American Heart Association, and the National Kidney Foundation of the Upper Midwest. Dr Guijarro is the recipient of awards from the Fondo de Investigacio ´n Sanitaria (Nr. 92/5510, 93/5439), Spanish Ministry of Health. Address reprint requests to Michael P. O’Donnell, PhD, Division of Nephrology, Hennepin County Medical Center, HFA Building, 5th Floor, 914 South 8th St, Minneapolis, MN 55404. E-mail:mod19@mail.idt.net  1998 by the National Kidney Foundation, Inc. 0272-6386/98/3101-0031$3.00/0 190 American Journal of Kidney Diseases, Vol 31, No 1 (January), 1998: pp 190-194