The combination of lovastatin and enalapril in a model of progressive renal disease

Abstract

Puromycin-induced nephrotic syndrome is an animal model of progressive renal disease. Both angiotensin converting enzyme inhibitors and lipid-lowering agents have been used to preserve renal structure and function in this model, although neither completely prevents progression. We tested the hypothesis that the combination of the two agents would be more protective than either alone. Rats were divided into five groups; all were uninephrectomized. Four groups were given puromycin at a dose of 10 mg/100 g body weight (BW) with additional doses of 4 mg/100 g BW given intraperitoneally at 4, 5, and 6 weeks thereafter. One group was given enalapril (EN) 50 mg/l dissolved in the drinking water; the second received lovastatin (L) 15 mg/kg given daily by gavage; the third received both agents; the fourth was left untreated, and the final group received no puromycin and served as the control group. Eight weeks after the initial dose of puromycin, glomerular filtration rate (GFR), as inulin clearance, and protein excretion were determined and blood was collected for cholesterol and triglycerides. Blood pressure was not different between any of the groups. At the end of the study period, serum cholesterol [mean ±SD, 252±185 mg/dl (L), 135±101 mg/dl (L+EN)] and triglycerides (239±200, 148±158 mg/dl) were significantly lower (P<0.001) in the lovastatintreated groups than in the untreated puromycin group (535±255 mg/dl and 579±561 mg/dl, cholesterol and triglyceride, respectively). Likewise protein excretion was significantly lower (P<0.001) in these groups also [507±336 (L), 253±331 (L+EN) vs. 745±381 (puromycin) mg/24 h]. Renal function was also preserved with a significantly better GFR per gram kidney weight in the lovastatin-treated groups [0.56±0.33 (L), 0.54±0.19 (L+EN) vs. 0.17±0.11 ml/min per gram]. Glomerulosclerosis, as measured by a sclerotic index, was also significantly less in the lovastatin plus enalapril-trated group (0.29±0.35) compared with the untreated puromycin group (2.29±0.54). Although enalapril had little effect by itself, the combination of enalapril and lovastatin appeared to significantly improve the decrease in serum cholesterol, triglyceride, and protein excretion. Thus treatment with lovastatin alone, and its subsequent lowering of serum cholesterol and triglyceride concentrations, improved renal structure and function in this model of puromycin nephrosis. The combination of lovastatin and enalapril resulted in the least histological damage, the least protein excretion, and preservation of GFR.