We examined the interrelation between systemic hypertension, hyperlipidemia, and progressive renal injury in experimental glomerulonephritis. Induction of nephrotoxic serum nephritis in Sprague-Dawley rats led to systemic hypertension and hyperlipidemia. Four groups of rats were studied over a 16-week period: (1) untreated nephritic rats; (2) nephritic rats treated with hydralazine, reserpine, and lasix (AH); (3) nephritic rats treated with lovastatin (4 mg/kg) (Lova); and (4) nephritic rats treated with combined antihypertensive/lipidlowering therapy (AH/Lova). Systolic blood pressure rose progressively in untreated rats (152±4 mm Hg at 16 weeks). Blood pressure was reduced by antihypertensive therapy (P<.001) (108±2 mmHg in the AH group and 111±3 mm Hg in the AH/Lova group) but remained elevated in animals treated with lovastatin alone (P>.05) (156±3 mmHg in the Lova group). Serum cholesterol rose progressively in untreated rats (3.70±0.85 mmol/L [143±33 mg/dL] at 16 weeks). The rise in serum cholesterol was prevented by lovastatin therapy (P<.001) (2.22±0.41 mmol/L [8 6±16 mg/dL] in the Lova group and 2.09±0.52 mmol/L [81 ±2 mg/dL] in the AH/Lova group) but not antihypertensive therapy (P>.05) (2.92±0.65 mmol/L [113±25 mg/dL] in the AH group). Proteinuria was reduced by antihypertensive therapy (P<.001) and lipid-lowering therapy (P<.05) (16-week values: 1.069±0.167 g/d in untreated rats, 0.663±0.164 g/d in the Lova group, 0.392±0.051 g/d in the AH group, and 0.176±0.035 g/d in the AH/Lova group). Glomerular injury score was significantly reduced by antihypertensive therapy (P<.01) and lipid-lowering therapy (P<.05). Glomerular injury score was lowest in animals receiving combined therapy, reflecting an interaction between these therapies (P<.01) (untreated, 173±29; Lova, 128±24; AH, 111±22; AH/Lova, 48±11). Our results suggest that both hypertension and hyperlipidemia accelerate glomerular sclerosis in experimental glomerulonephritis and that combined therapy of these disorders may best limit progressive renal injury.