Preventive effect of lactacystin, a selective proteasome inhibitor, on ischemic acute renal failure in rats

To elucidate the role of a proteasome-dependent proteolytic pathway in the pathogenesis of acute renal failure (ARF), we examined the effect of a sele ctive proteasome inhibitor, lactacystin, on ARF induced by ischemia/reperfu sion. Ischemic ARF was induced by clamping the left renal artery and vein f or 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in untreated ARF rats markedly decreased at 24 h after repe rfusion. Intraperitoneal injection of lactacystin at a dose of 0.1 mg/kg be fore the occlusion tended to attenuate the deterioration of renal function. The higher dose of lactacystin (1 mg/kg) markedly attenuated the ischemia/ reperfusion-induced renal dysfunction. Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necr osis, proteinaceous casts in tubuli, and medullary congestion, all of which were markedly suppressed by the higher dose of lactacystin. In addition, e ndothelin (ET)-1 content in the kidney after the ischemia/reperfusion was s ignificantly increased, being the maximum level at 6 h after the reperfusio n, and this elevation was abolished by the higher dose of lactacystin. Thes e results indicate that lactacystin prevents the development of ischemia/re perfusion-induced ARF, and the effect is accompanied by suppression of the enhanced ET-1 production in the kidney, thereby suggesting that a proteasom e-dependent proteolytic pathway has a crucial role in the pathogenesis of i schemic ARF, possibly through the enhancement of ET-1 production in postisc hemic kidneys.