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Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat
P K Chatterjee1, P A Brown, S Cuzzocrea
1Department 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
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.
Insights
Calpain inhibitor-1 (Cal I-1) effectively reduced kidney dysfunction and injury in a rat model of renal ischemia/reperfusion (I/R) injury. This protective effect may stem from inhibiting nuclear factor-kappa B (NF-kappa B) activation.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Calpain activation is linked to renal ischemia/reperfusion (I/R) injury.
- This study investigated calpain inhibitor-1 (Cal I-1) in a rat model of renal I/R injury.
Purpose of the Study:
- To evaluate the therapeutic potential of Cal I-1 in mitigating renal I/R injury.
- To elucidate the mechanisms underlying Cal I-1's protective effects.
Main Methods:
- Rats received Cal I-1 before bilateral renal ischemia and reperfusion.
- Renal function markers (urea, creatinine, C(Cr), FE(Na)), oxidative stress markers (MDA), neutrophil infiltration (MPO), and inflammatory markers (iNOS, COX-2) were assessed.
- Histological analysis was performed to grade renal injury.
Main Results:
- Cal I-1 significantly improved renal function markers and reduced markers of oxidative stress and neutrophil infiltration.
- Histological examination revealed reduced renal damage in Cal I-1 treated rats.
- Cal I-1 treatment substantially decreased the expression of iNOS and COX-2, suggesting NF-kappa B pathway involvement.
Conclusions:
- Cal I-1 demonstrates significant renoprotective effects against I/R injury.
- The findings suggest that Cal I-1's mechanism involves the inhibition of I/R-mediated NF-kappa B activation.