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

P.K. Chatterjee, Z. Todoric, A. Sivarajah, H. Mota-Filipe, P.A.J. Brown, K.N. Stewart, S. Cuzzocrea, C. Thiemermann

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)173-183
Number of pages11
JournalEuropean Journal of Pharmacology
Volume503
Issue number1-3
DOIs
Publication statusPublished - Oct 2004

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Caspase Inhibitors
Kidney
Wounds and Injuries
Caspase 3
Caspase 1
Caspases
Acute Kidney Injury
Constriction
Reperfusion
Creatinine
Oxidative Stress
Cell Death
Necrosis

Keywords

  • Renal/kidney
  • Ischemia
  • Reperfusion injury
  • Caspase
  • Caspase inhibitor

Cite this

Chatterjee, P.K. ; Todoric, Z. ; Sivarajah, A. ; Mota-Filipe, H. ; Brown, P.A.J. ; Stewart, K.N. ; Cuzzocrea, S. ; Thiemermann, C. / Differential effects of caspase inhibitors on the renal dysfunction and injury caused by ischemia–reperfusion of the rat kidney. In: European Journal of Pharmacology. 2004 ; Vol. 503, No. 1-3. pp. 173-183.
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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.; Thiemermann, C.

In: European Journal of Pharmacology, Vol. 503, No. 1-3, 10.2004, p. 173-183.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Differential effects of caspase inhibitors on the renal dysfunction and injury caused by ischemia–reperfusion of the rat kidney

AU - Chatterjee, P.K.

AU - Todoric, Z.

AU - Sivarajah, A.

AU - Mota-Filipe, H.

AU - Brown, P.A.J.

AU - Stewart, K.N.

AU - Cuzzocrea, S.

AU - Thiemermann, C.

PY - 2004/10

Y1 - 2004/10

N2 - 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.

AB - 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.

KW - Renal/kidney

KW - Ischemia

KW - Reperfusion injury

KW - Caspase

KW - Caspase inhibitor

U2 - 10.1016/j.ejphar.2004.09.025

DO - 10.1016/j.ejphar.2004.09.025

M3 - Article

VL - 503

SP - 173

EP - 183

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

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ER -