Inhibitors of calpain activation (PD150606 and E-64) and renal ischemia-reperfusion injury

P K Chatterjee, Z Todorovic, A Sivarajah, H Mota-Filipe, P A J Brown, K N Stewart, E Mazzon, S Cuzzocrea, C Thiemermann

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Abstract

Calpain activation has been implicated in the development of ischemia-reperfusion (I-R) injury. Here we investigate the effects of two inhibitors of calpain activity, PD150606 and E-64, on the renal dysfunction and injury caused by I-R of rat kidneys in vivo. Male Wistar rats were administered PD150606 or E-64 (3 mg/kg i.p.) or vehicle (10%, v/v, DMSO) 30 min prior to I-R. Rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion (6 h). Serum and urinary biochemical indicators of renal dysfunction and injury were measured; serum creatinine (for glomerular dysfunction), fractional excretion of Na+ (FENa, for tubular dysfunction) and urinary N-acetyl-beta-D-glucosaminidase (NAG, for tubular injury). Additionally, kidney tissues were used for histological analysis of renal injury, immunohistochemical analysis of intercellular adhesion molecule-1 (ICAM-1) expression and nitrotyrosine formation. Renal myeloper-oxidase (MPO) activity (for polymorphonuclear leukocyte infiltration) and malondialdehyde (MDA) levels (for tissue lipid peroxidation) were determined. Both PD150606 and E-64 significantly reduced the increases in serum creatinine, FENa and NAG caused by renal I-R, indicating attenuation of renal dysfunction and injury and reduced histological evidence of renal damage caused by I-R. Both PD150606 and E-64 markedly reduced the evidence of oxidative stress (ICAM-1 expression, MPO activity, MDA levels) and nitrosative stress (nitrotyrosine formation) in rat kidneys subjected to I-R. These findings provide the first evidence that calpain inhibitors can reduce the renal dysfunction and injury caused by I-R of the kidney and may be useful in enhancing the tolerance of the kidney against renal injury associated with aortovascular surgery or renal transplantation. (c) 2005 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)1121-1131
Number of pages11
JournalBiochemical Pharmacology
Volume69
DOIs
Publication statusPublished - 2005

Keywords

  • renal/kidney
  • ischemia
  • reperfusion-injury
  • calpain inhibitor
  • PD150606
  • E-64
  • NF-KAPPA-B
  • PROXIMAL TUBULAR INJURY
  • TRANSIENT FOREBRAIN ISCHEMIA
  • NITRIC-OXIDE SYNTHASE
  • CELL-DEATH
  • ISCHEMIA/REPERFUSION INJURY
  • CYSTEINE PROTEASES
  • ARTERY-OCCLUSION
  • RAT-KIDNEY
  • DYSFUNCTION

Cite this

Chatterjee, P. K., Todorovic, Z., Sivarajah, A., Mota-Filipe, H., Brown, P. A. J., Stewart, K. N., ... Thiemermann, C. (2005). Inhibitors of calpain activation (PD150606 and E-64) and renal ischemia-reperfusion injury. Biochemical Pharmacology, 69, 1121-1131. https://doi.org/10.1016/j.bcp.2005.01.003

Inhibitors of calpain activation (PD150606 and E-64) and renal ischemia-reperfusion injury. / Chatterjee, P K ; Todorovic, Z ; Sivarajah, A ; Mota-Filipe, H ; Brown, P A J ; Stewart, K N ; Mazzon, E ; Cuzzocrea, S ; Thiemermann, C .

In: Biochemical Pharmacology, Vol. 69, 2005, p. 1121-1131.

Research output: Contribution to journalArticle

Chatterjee, PK, Todorovic, Z, Sivarajah, A, Mota-Filipe, H, Brown, PAJ, Stewart, KN, Mazzon, E, Cuzzocrea, S & Thiemermann, C 2005, 'Inhibitors of calpain activation (PD150606 and E-64) and renal ischemia-reperfusion injury', Biochemical Pharmacology, vol. 69, pp. 1121-1131. https://doi.org/10.1016/j.bcp.2005.01.003
Chatterjee PK, Todorovic Z, Sivarajah A, Mota-Filipe H, Brown PAJ, Stewart KN et al. Inhibitors of calpain activation (PD150606 and E-64) and renal ischemia-reperfusion injury. Biochemical Pharmacology. 2005;69:1121-1131. https://doi.org/10.1016/j.bcp.2005.01.003
Chatterjee, P K ; Todorovic, Z ; Sivarajah, A ; Mota-Filipe, H ; Brown, P A J ; Stewart, K N ; Mazzon, E ; Cuzzocrea, S ; Thiemermann, C . / Inhibitors of calpain activation (PD150606 and E-64) and renal ischemia-reperfusion injury. In: Biochemical Pharmacology. 2005 ; Vol. 69. pp. 1121-1131.
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N2 - Calpain activation has been implicated in the development of ischemia-reperfusion (I-R) injury. Here we investigate the effects of two inhibitors of calpain activity, PD150606 and E-64, on the renal dysfunction and injury caused by I-R of rat kidneys in vivo. Male Wistar rats were administered PD150606 or E-64 (3 mg/kg i.p.) or vehicle (10%, v/v, DMSO) 30 min prior to I-R. Rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion (6 h). Serum and urinary biochemical indicators of renal dysfunction and injury were measured; serum creatinine (for glomerular dysfunction), fractional excretion of Na+ (FENa, for tubular dysfunction) and urinary N-acetyl-beta-D-glucosaminidase (NAG, for tubular injury). Additionally, kidney tissues were used for histological analysis of renal injury, immunohistochemical analysis of intercellular adhesion molecule-1 (ICAM-1) expression and nitrotyrosine formation. Renal myeloper-oxidase (MPO) activity (for polymorphonuclear leukocyte infiltration) and malondialdehyde (MDA) levels (for tissue lipid peroxidation) were determined. Both PD150606 and E-64 significantly reduced the increases in serum creatinine, FENa and NAG caused by renal I-R, indicating attenuation of renal dysfunction and injury and reduced histological evidence of renal damage caused by I-R. Both PD150606 and E-64 markedly reduced the evidence of oxidative stress (ICAM-1 expression, MPO activity, MDA levels) and nitrosative stress (nitrotyrosine formation) in rat kidneys subjected to I-R. These findings provide the first evidence that calpain inhibitors can reduce the renal dysfunction and injury caused by I-R of the kidney and may be useful in enhancing the tolerance of the kidney against renal injury associated with aortovascular surgery or renal transplantation. (c) 2005 Elsevier Inc. All rights reserved.

AB - Calpain activation has been implicated in the development of ischemia-reperfusion (I-R) injury. Here we investigate the effects of two inhibitors of calpain activity, PD150606 and E-64, on the renal dysfunction and injury caused by I-R of rat kidneys in vivo. Male Wistar rats were administered PD150606 or E-64 (3 mg/kg i.p.) or vehicle (10%, v/v, DMSO) 30 min prior to I-R. Rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion (6 h). Serum and urinary biochemical indicators of renal dysfunction and injury were measured; serum creatinine (for glomerular dysfunction), fractional excretion of Na+ (FENa, for tubular dysfunction) and urinary N-acetyl-beta-D-glucosaminidase (NAG, for tubular injury). Additionally, kidney tissues were used for histological analysis of renal injury, immunohistochemical analysis of intercellular adhesion molecule-1 (ICAM-1) expression and nitrotyrosine formation. Renal myeloper-oxidase (MPO) activity (for polymorphonuclear leukocyte infiltration) and malondialdehyde (MDA) levels (for tissue lipid peroxidation) were determined. Both PD150606 and E-64 significantly reduced the increases in serum creatinine, FENa and NAG caused by renal I-R, indicating attenuation of renal dysfunction and injury and reduced histological evidence of renal damage caused by I-R. Both PD150606 and E-64 markedly reduced the evidence of oxidative stress (ICAM-1 expression, MPO activity, MDA levels) and nitrosative stress (nitrotyrosine formation) in rat kidneys subjected to I-R. These findings provide the first evidence that calpain inhibitors can reduce the renal dysfunction and injury caused by I-R of the kidney and may be useful in enhancing the tolerance of the kidney against renal injury associated with aortovascular surgery or renal transplantation. (c) 2005 Elsevier Inc. All rights reserved.

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KW - NITRIC-OXIDE SYNTHASE

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KW - ISCHEMIA/REPERFUSION INJURY

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