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 i nvestigate 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 minu tes before undergoing bilateral renal ischemia (45 minutes) followed by rep erfusion (6 hours). Plasma concentrations of urea, creatinine, Na+, gamma - glutamyl transferase (gamma GT), aspartate aminotransferase (AST) and urina ry Na+ glutathione S-transferase (GST), and N-acetyl-beta -D-glucosaminidas e (NAG) were measured for the assessment of renal dysfunction and I/R injur y. Creatinine clearance (C-Cr) and fractional excretion of Na+ (FENa) were used as indicators of glomerular and tubular function, respectively. Kidney myeloperoxidase (MPO) activity and malondialdehyde (MI)A) levels were meas ured for assessment of neutrophil infiltration and lipid peroxidation, resp ectively. Renal sections were used for histologic grading of renal injury a nd 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, crea tinine, gamma GT, AST, NAG, and FENa and significantly improved C-Cr. Cal I -1 also significantly reduced kidney MPO activity and MDA levels. Cal I-1 a lso reduced histologic evidence of I/R-mediated renal damage and caused a s ubstantial reduction in the expression of iNOS and COX-2, both of which inv olve activation of nuclear factor-kappaB (NF-kappaB). Conclusions. These results suggest that Cal I-1 reduces the renal dysfuncti on and injury associated with I/R of the kidney. We suggest that the mechan ism could involve the inhibition of I/R-mediated activation of NF-kappaB.