This study was undertaken to determine the role of angiotensin II (AII) in the development of glomerulosclerosis, using an AII receptor antagonist in an animal model of hyperlipidemia. Hyperlipidemic Imai rats were employed because they spontaneously develop glomerulosclerosis; this is especially true in males. Group 1 (n = 5) received no specific therapy. Group 2 (n = 5) was treated with enalapril at a dosage of 50 mg/l in drinking water starting at 6 weeks of age. Group 3 (n = 5) and group 4 (n = 6) were treated with the AII receptor antagonist DuP 753 at a respective dosage of 15 mg/l (low-dose DuP) and 150 mg/l (high-dose DuP) in drinking water. Body weight, blood pressure, urinary protein, serum albumin, cholesterol, BUN and serum creatinine were measured and compared among the groups from 12 to 24 weeks of age. Enalapril and high-dose DuP were almost equally effective in controlling systemic hypertension. Each treatment significantly reduced proteinuria (172 + 112 and 152 ± 72 mg/kg/day at 24 weeks) as compared with that in the controls (421 ± 147 mg/kg/day; p < 0.05 and p < 0.0l, respectively). Hypercholesterolemia also decreased (82 ± 4 and 89 ± 6 mg/dl) as compared with that of the controls (141 ± 48 mg/dl; both p < 0.05). Glomerulosclerosis index (SI) was significantly higher in the untreated control rats (55 ± 26) than in the enalapril-treated rats (2 ± 3; p < 0.005) and the high-dose-DuP-treated rats (6 ± 6, p < 0.005). Low-dose-DuP-treated rats showed lower proteinuria (217 ± 83 vs. 421 ± 147 mg/kg/ day; p < 0.05) and a lower SI (19 ± 5 vs. 55 ± 26; p < 0.01) than did the untreated control rats, although there was no significant difference in systemic hypertension between the two groups. These results, which show a sharp contrast between the effects of an AII receptor antagonist on blood pressure and renal injury, suggest that AII is involved in the development of glomerulosclerosis even in hyperlipidemic Imai rats.