Proteasome participates in the pathogenesis of ischemic acute renal failure in rats

Acute renal failure was induced by occlusion of the left renal artery and v ein for 45 min followed by reperfusion, 2 weeks after contralateral nephrec tomy. Renal function parameters such as blood urea nitrogen, plasma creatin ine, creatinine clearance, urine flow and urinary osmolality were measured to test the effectiveness of drugs. Renal function in untreated acute renal failure rats markedly decreased at 24 h after reperfusion. The administrat ion of PSI, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, a proteasome inhibitor, at a dose of 1 mg/kg before the occlusion abolished the decrease s in the renal function of acute renal failure rats. Calpeptin (1 mg/kg), a calpain inhibitor, attenuated the deterioration of renal function to the s ame extent as 0.1 mg/kg PSI, but no significant difference was observed bet ween the untreated and calpeptin-treated acute renal failure groups. Histop athological examination of the kidney of untreated acute renal failure rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were significantly suppressed by PSI (1 mg/kg) treatment. In contrast, calpeptin, at the same dose, was ineffective against the development of renal lesions. These results suggest that proteasome participates in the pathogenesis of ischemic acute renal f ailure. Thus, proteasome may be a potential target for the identification o f agents that may be useful in the treatment of diseases whose etiology is dependent on ischemia/reperfusion. (C) 1999 Elsevier Science B.V. All right s reserved.