Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat.
BACKGROUND
Activation of the cysteine protease calpain has been implicated in renal ischemia/reperfusion (I/R) injury. The aim of this study was to investigate the effects of calpain inhibitor-1 (Cal I-1) in an in vivo model of renal I/R injury.


METHODS
Male Wistar rats were administered Cal I-1 (10 mg/kg, IP) 30 minutes before undergoing bilateral renal ischemia (45 minutes) followed by reperfusion (6 hours). Plasma concentrations of urea, creatinine, Na(+), gamma-glutamyl transferase (gamma GT), aspartate aminotransferase (AST) and urinary Na(+), glutathione S-transferase (GST), and N-acetyl-beta-D-glucosaminidase (NAG) were measured for the assessment of renal dysfunction and I/R injury. Creatinine clearance (C(Cr)) and fractional excretion of Na(+) (FE(Na)) were used as indicators of glomerular and tubular function, respectively. Kidney myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels were measured for assessment of neutrophil infiltration and lipid peroxidation, respectively. Renal sections were used for histologic grading of renal injury and for immunohistochemical localization of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2).


RESULTS
Cal I-1 significantly reduced I/R-mediated increases in urea, creatinine, gamma GT, AST, NAG, and FE(Na) and significantly improved C(Cr). Cal I-1 also significantly reduced kidney MPO activity and MDA levels. Cal I-1 also reduced histologic evidence of I/R-mediated renal damage and caused a substantial reduction in the expression of iNOS and COX-2, both of which involve activation of nuclear factor-kappa B (NF-kappa B).


CONCLUSIONS
: These results suggest that Cal I-1 reduces the renal dysfunction and injury associated with I/R of the kidney. We suggest that the mechanism could involve the inhibition of I/R-mediated activation of NF-kappa B.
Chatterjee
P K
PK
Department of Experimental Medicine and Nephrology, The William Harvey Research Institute, and the Royal London School of Medicine and Dentistry, London, England, United Kingdom. p.k.chaterjee@mds.qmw.ac.uk
Brown
P A
PA
Cuzzocrea
S
S
Zacharowski
K
K
Stewart
K N
KN
Mota-Filipe
H
H
McDonald
M C
MC
Thiemermann
C
C
D000118:Acetylglucosaminidase / Q000652:urine; D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000758:Anesthesia; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D051546:Cyclooxygenase 2; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000652:urine; D006023:Glycoproteins / Q000494:pharmacology*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism; D007678:Kidney Glomerulus / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009842:Oligopeptides / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D005723:gamma-Glutamyltransferase / Q000097:blood
D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; D007527:Isoenzymes; D016328:NF-kappa B; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; C039304:calpain inhibitors; D008315:Malondialdehyde; C002101:chymostatin; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000118:Acetylglucosaminidase