Inhibitors of calpain activation (PD150606 and E-64) and renal ischemia-reperfusion injury.
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.
Chatterjee
Prabal K
PK
Centre for Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute, Queen Mary-University of London, London, UK. p.k.chatterjee@brighton.ac.uk <p.k.chatterjee@brighton.ac.uk>
Todorovic
Zoran
Z
Sivarajah
Ahila
A
Mota-Filipe
Helder
H
Brown
Paul A J
PA
Stewart
Keith N
KN
Mazzon
Emanuela
E
Cuzzocrea
Salvatore
S
Thiemermann
Christoph
C
D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors*; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects*; D015427:Reperfusion Injury / Q000517:prevention & control*
D000179:Acrylates; D015853:Cysteine Proteinase Inhibitors; C100442:PD 150606; D002403:Cathepsins; D002154:Calpain; D007930:Leucine; C024974:E 64