Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat

P. K. Chatterjee, Paul Anthony James Brown, K. Zacharowski, S. Cuzzocrea, Keith Nicol Stewart, H. Mota-Filipe, M. C. McDonald, C. Thiemermann

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Abstract

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+ (FENa) were used as indicators of glomerular and tubular function, respectively. Kidney myeloperoxidase (MPO) activity and malondialdehyde (MI)A) 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 FENa 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-kappaB (NF-kappaB).

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-kappaB.

Original languageEnglish
Pages (from-to)2073-2083
Number of pages10
JournalKidney International
Volume59
Issue number6
Publication statusPublished - 2001

Keywords

  • kidney injury
  • inducible nitric oxide synthase
  • COX-2
  • nuclear factor-kappa B
  • acute renal failure
  • NITRIC-OXIDE SYNTHASE
  • NF-KAPPA-B
  • ISCHEMIA-REPERFUSION INJURY
  • PROXIMAL TUBULAR INJURY
  • CYSTEINE PROTEASES
  • KIDNEY
  • PROTEOLYSIS
  • FAILURE
  • DAMAGE
  • INFILTRATION

Cite this

Chatterjee, P. K., Brown, P. A. J., Zacharowski, K., Cuzzocrea, S., Stewart, K. N., Mota-Filipe, H., McDonald, M. C., & Thiemermann, C. (2001). Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat. Kidney International, 59(6), 2073-2083.