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

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 (3mg/kg i.p.) or vehicle (10%, v/v, DMSO) 30min prior to I-R. Rats were subjected to bilateral renal ischemia (45min) followed by reperfusion (6h). Serum and urinary biochemical indicators of renal dysfunction and injury were measured; serum creatinine (for glomerular dysfunction), fractional excretion of Na(+) (FE(Na), 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 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, FE(Na) 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.

• Authors: Prabal K Chatterjee, Zoran Todorovic, Ahila Sivarajah, Helder Mota-Filipe, Paul A J Brown, Keith N Stewart, Emanuela Mazzon, Salvatore Cuzzocrea, Christoph Thiemermann
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 69 Issue 7 Pg. 1121-31 (Apr 01 2005) ISSN: 0006-2952 [Print] England
• PMID: 15763548 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acrylates
• Cysteine Proteinase Inhibitors
• PD 150606
• Cathepsins
• Calpain
• Leucine
• E 64

Topics

• Acrylates (pharmacology)
• Animals
• Calpain (antagonists & inhibitors)
• Cathepsins (antagonists & inhibitors)
• Cysteine Proteinase Inhibitors (pharmacology)
• Kidney (blood supply, pathology)
• Leucine (analogs & derivatives, pharmacology)
• Male
• Rats
• Rats, Wistar
• Renal Circulation (drug effects)
• Reperfusion Injury (prevention & control)