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

Chatterjee, P.K., Todoric, Z., Sivarajah, A., Mota-Filipe, H., Brown, P.A.J., Stewart, K.N., Cuzzocrea, S. and Thiemermann, C. (2004) Differential effects of caspase inhibitors on the renal dysfunction and injury caused by ischemia–reperfusion of the rat kidney European Journal of Pharmacology, 503 (1-3). pp. 173-183.

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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.

Item Type: Journal article
Uncontrolled Keywords: Renal/kidney; Ischemia; Reperfusion injury; Caspase; Caspase inhibitor
Subjects: B000 Health Professions > B100 Anatomy Physiology and Pathology
DOI (a stable link to the resource): 10.1016/j.ejphar.2004.09.025
Faculties: Faculty of Science and Engineering > School of Pharmacy and Biomolecular Sciences
Depositing User: editor spbs
Date Deposited: 06 Nov 2007
Last Modified: 05 Jun 2013 10:20
URI: http://eprints.brighton.ac.uk/id/eprint/429

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