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Differential effects of caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney.

Abstract
Caspase activation has been implicated in the development of ischemia-reperfusion injury. Here, we investigate the effects of different caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney. Bilateral clamping of renal pedicles (45 min) followed by reperfusion (6 h) caused significant renal dysfunction and marked renal injury. Caspase-1 inhibitor II (N-acetyl-L-tyrosyl-L-valyl-N-[(1S)-1-(carboxymethyl)-3-chloro-2-oxo-propyl]-L-alaninamide, Ac-YVAD-CMK, 3 mg/kg, administered i.p.) significantly reduced biochemical and histological evidence of renal dysfunction and injury. However, although caspase-3 inhibitor I (N-acetyl-L-aspartyl-L-glutamyl-N-(2-carboxyl-1-formylethyl]-L-valinamide, Ac-DEVD-CHO, 3 mg/kg, administered i.p.) produced a significant improvement of renal (glomerular) dysfunction (reduction of serum creatinine levels), it was not able to reduce tubular dysfunction and injury. Furthermore, the pan-caspase inhibitor caspase inhibitor III (N-tert-butoxycarbonyl-aspartyl(OMe)-fluoromethylketone, Boc-D-FMK, 3 mg/kg, administered i.p.) did not reduce renal dysfunction and injury. Both caspase-1 and -3 inhibitors markedly reduced the evidence of oxidative and nitrosative stress in rat kidneys subjected to ischemia-reperfusion. Overall, these results demonstrate that inhibition of caspase-1 reduces renal ischemia-reperfusion injury to a greater extent than caspase-3 inhibition, supporting the notion that the mode of acute cell death in our model of renal ischemia-reperfusion is primarily via necrosis. Furthermore, our finding that a pan-caspase inhibitor did not reduce the renal dysfunction and injury suggests that activation of some caspases during ischemia-reperfusion could provide protection against acute ischemic renal injury. Overall, these results demonstrate that inhibition of caspase-1 activity reduces renal ischemia-reperfusion injury and that this therapeutic strategy may be of benefit against ischemic acute renal failure.
AuthorsPrabal K Chatterjee, Zoran Todorovic, Ahila Sivarajah, Helder Mota-Filipe, Paul A J Brown, Keith N Stewart, Salvatore Cuzzocrea, Christoph Thiemermann
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 503 Issue 1-3 Pg. 173-83 (Oct 25 2004) ISSN: 0014-2999 [Print] Netherlands
PMID15496312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzyl Compounds
  • Biomarkers
  • Boc-D-FMK
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Hydrocarbons, Fluorinated
  • Oligopeptides
  • Serpins
  • Viral Proteins
  • acetyl-aspartyl-glutamyl-valyl-aspartal
  • Intercellular Adhesion Molecule-1
  • Nitric Oxide
  • 3-nitrotyrosine
  • Tyrosine
  • Malondialdehyde
  • interleukin-1beta-converting enzyme inhibitor
  • Peroxidase
  • Casp3 protein, rat
  • Caspase 3
Topics
  • Animals
  • Benzyl Compounds (pharmacology)
  • Biomarkers
  • Caspase 3
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors (pharmacology)
  • Hydrocarbons, Fluorinated (pharmacology)
  • Immunohistochemistry
  • In Vitro Techniques
  • Intercellular Adhesion Molecule-1 (metabolism)
  • Kidney (physiopathology)
  • Kidney Function Tests
  • Male
  • Malondialdehyde (metabolism)
  • Myocardium (pathology)
  • Nitric Oxide (physiology)
  • Oligopeptides (pharmacology)
  • Organ Size (drug effects)
  • Oxidative Stress (drug effects)
  • Peroxidase (metabolism)
  • Rats
  • Rats, Wistar
  • Reperfusion Injury (drug therapy, pathology, physiopathology)
  • Serpins (pharmacology)
  • Tyrosine (analogs & derivatives, metabolism)
  • Viral Proteins (pharmacology)

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