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 selective proteasome inhibitor, lactacystin, on ARF induced by ischemia/reperfusion. Ischemic ARF was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion. Intraperitoneal injection of lactacystin at a dose of 0.1 mg/kg before 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 necrosis, proteinaceous casts in tubuli, and medullary congestion, all of which were markedly suppressed by the higher dose of lactacystin. In addition, endothelin (ET)-1 content in the kidney after the ischemia/reperfusion was significantly increased, being the maximum level at 6 h after the reperfusion, and this elevation was abolished by the higher dose of lactacystin. These results indicate that lactacystin prevents the development of ischemia/reperfusion-induced ARF, and the effect is accompanied by suppression of the enhanced ET-1 production in the kidney, thereby suggesting that a proteasome-dependent proteolytic pathway has a crucial role in the pathogenesis of ischemic ARF, possibly through the enhancement of ET-1 production in postischemic kidneys.
Itoh
M
M
Department of Pharmaceutical, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan.
Takaoka
M
M
Shibata
A
A
Ohkita
M
M
Matsumura
Y
Y
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058186:Acute Kidney Injury / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001806:Blood Urea Nitrogen; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D019332:Endothelin-1 / Q000378:metabolism; D007511:Ischemia / Q000473:pathology*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control
D015853:Cysteine Proteinase Inhibitors; D019332:Endothelin-1; D009097:Multienzyme Complexes; C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine