Proteasome inhibition attenuates renal endothelin-1 production and the development of ischemic acute renal failure in rats

The objectives of this study were (1) to assess the role of a proteasome-de pendent proteolytic pathway in the pathogenesis of acute renal failure (ARF ) induced by ischemia-reperfusion, and (2) to determine the involvement of this proteolytic pathway in the enhanced production of renal endothelin-1 ( ET-1) in this model of ARE ARF was induced by clamping the left renal arter y and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow, urinary osmolality and fracti onal excretion of sodium were measured to test the effectiveness of drugs u sed. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion. In addition, a marked increase in renal ET-1 content was evide nt in the ARF rats, compared to the sham-operated rats. Intraperitoneal inj ection of a proteasome inhibitor (PSI), N-benzyloxycarbonyl-Ile-Glu(O-t-Bu) -Ala-leucinal, at a dose of 1 mg/kg, 1 h before the clamping, significantly attenuated the renal function impairment in the ischemic ARF rats, and the effect was accompanied by a decrease in renal ET-1 content. On the other h and, a calpain inhibitor, calpeptin, had little effect at the same dose. Th ese results suggest that a proteasome-dependent proteolytic pathway is invo lved in the enhanced production of ET-1 in the kidney and the consequent re nal functional damage in ischemic ARF.