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

Prabal K. Chatterjee, Zoran Todorovic, Ahila Sivarajah, Helder Mota-Filipe, Paul A J Brown, Keith N. Stewart, Emanuela Mazzon, Salvatore Cuzzocrea, Christoph Thiemermann

Research output: Contribution to journalArticle

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-β-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 myeloperoxidase (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.

Original languageEnglish
Pages (from-to)1121-1131
Number of pages11
JournalBiochemical Pharmacology
Volume69
Issue number7
DOIs
Publication statusPublished - Apr 1 2005

Keywords

  • Calpain inhibitor
  • E-64
  • Ischemia
  • PD150606
  • Renal/kidney
  • Reperfusion-injury

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    Chatterjee, P. K., Todorovic, Z., Sivarajah, A., Mota-Filipe, H., Brown, P. A. J., Stewart, K. N., Mazzon, E., Cuzzocrea, S., & Thiemermann, C. (2005). Inhibitors of calpain activation (PD150606 and E-64) and renal ischemia-reperfusion injury. Biochemical Pharmacology, 69(7), 1121-1131. https://doi.org/10.1016/j.bcp.2005.01.003