Document Detail

Proteasome inhibition attenuates renal endothelin-1 production and the development of ischemic acute renal failure in rats.
MedLine Citation:
PMID:  11078383     Owner:  NLM     Status:  MEDLINE    
The objectives of this study were (1) to assess the role of a proteasome-dependent 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 ARF. ARF was induced by clamping the left renal artery 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 fractional excretion of sodium were measured to test the effectiveness of drugs used. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion. In addition, a marked increase in renal ET-1 content was evident in the ARF rats, compared to the sham-operated rats. Intraperitoneal injection 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 hand, a calpain inhibitor, calpeptin, had little effect at the same dose. These results suggest that a proteasome-dependent proteolytic pathway is involved in the enhanced production of ET-1 in the kidney and the consequent renal functional damage in ischemic ARF.
M Takaoka; M Itoh; S Kohyama; A Shibata; M Ohkita; Y Matsumura
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  36     ISSN:  0160-2446     ISO Abbreviation:  J. Cardiovasc. Pharmacol.     Publication Date:  2000 Nov 
Date Detail:
Created Date:  2001-02-20     Completed Date:  2001-02-22     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  S225-7     Citation Subset:  IM    
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.
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MeSH Terms
Cysteine Endopeptidases / physiology*
Endothelin-1 / biosynthesis*
Ischemia / etiology*
Kidney / blood supply,  metabolism*
Kidney Failure, Acute / etiology*,  prevention & control
Multienzyme Complexes / physiology*
Proteasome Endopeptidase Complex
Rats, Sprague-Dawley
Reg. No./Substance:
0/Endothelin-1; 0/Multienzyme Complexes; EC 3.4.22.-/Cysteine Endopeptidases; EC Endopeptidase Complex

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