Lovastatin reduces glomerular macrophage influx and expression of monocyte chemoattractant protein-1 mRNA in nephrotic rats.
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 i.v. injection of PA (50 mg/kg) and continued to receive daily lovastatin thereafter. The vehicle-pretreated rats received i.v. injections of either PA or saline, and continued to receive daily vehicle treatment thereafter. Ten days after PA injection, the vehicle-treated PA rats showed increased (P < 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 < 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.
Park
Y S
YS
Department of Medicine, Hennepin County Medical Center, Minneapolis, MN 55404, USA.
Guijarro
C
C
Kim
Y
Y
Massy
Z A
ZA
Kasiske
B L
BL
Keane
W F
WF
O'Donnell
M P
MP
D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008148:Lovastatin / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D009401:Nephrosis / Q000139:chemically induced / Q000188:drug therapy*; D016133:Polymerase Chain Reaction; D011692:Puromycin Aminonucleoside; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D011692:Puromycin Aminonucleoside; D008148:Lovastatin