Lovastatin retards the progression of established glomerular disease in obese Zucker rats.
Considerable experimental evidence indicates that hyperlipidemia can induce glomerular injury. The importance of lipids in the progression of established glomerular disease has not been established and is of clinical relevance because of the frequent association of lipid abnormalities with human renal disease. In the present study, 26-week-old hyperlipidemic obese Zucker rats (OZRs) with established nephropathy were treated for a period of 18 weeks with daily injections of the cholesterol synthesis inhibitor lovastatin (4 mg/kg). Compared with control OZRs treated with vehicle, lovastatin-treated OZRs had significantly (P < 0.05) lower serum cholesterol and triglyceride levels throughout the treatment period. Blood pressure and urine albumin excretion in lovastatin-treated OZRs were reduced over the first 12 weeks of therapy, but increased toward the levels in the control OZRs at the end of the protocol. After 18 weeks of therapy, the incidence of glomerulosclerosis in lovastatin-treated OZRs (23.2% +/- 5.8%) was approximately half of that in vehicle-treated OZRs (44.6% +/- 7.7%) (P < 0.05). The reduction in glomerular injury in lovastatin-treated OZRs was not associated with changes in either glomerular area or glomerular macrophage content. In separate experiments, mesangial cells were cultured from glomeruli isolated from 26-week-old proteinuric OZRs. Lovastatin (5 to 40 mumol/L) caused a significant dose-dependent inhibition of serum-stimulated mesangial cell DNA synthesis. The inhibitory effects of lovastatin were completely prevented in the presence of exogenous mevalonate (100 mumol/L). Thus, lovastatin retarded the progression of established glomerular disease in OZRs.(ABSTRACT TRUNCATED AT 250 WORDS)
O'Donnell
M P
MP
Department of Medicine, Hennepin County Medical Center, Minneapolis, MN.
Kasiske
B L
BL
Kim
Y
Y
Schmitz
P G
PG
Keane
W F
WF
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005920:Glomerular Mesangium / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006949:Hyperlipidemias / Q000150:complications; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009765:Obesity / Q000150:complications; D051381:Rats; D011924:Rats, Zucker; D013997:Time Factors
D008148:Lovastatin