ToxSci Advance Access published online on January 27, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn008
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Role of Tissue Kallikrein in Prevention and Recovery of Gentamicin-induced Renal Injury
* Department of Biology, Charleston Southern University, Charleston, South Carolina
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina
Address Correspondence to:Grant Bledsoe, Ph.D, Department of Biology, Charleston Southern University, 9200 University Blvd, Charleston, SC 29406, Phone: 843-863-8085, Fax No: 843-863-7290, email: gbledsoe{at}csuniv.edu
Received November 14, 2007; revision received December 20, 2007; accepted December 20, 2007
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Abstract |
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Gentamicin is an aminoglycoside antibiotic that induces severe nephrotoxicity and acute renal failure. In the current project, we investigated the protective effects of tissue kallikrein (TK) protein administration (1 µg h-1 via osmotic minipumps) on kidney damage, apoptosis and inflammation both during and after a ten-day regimen of gentamicin (80 mg kg-1 body weight per day sc) in Sprague-Dawley rats. TK infusion during gentamicin treatment significantly attenuated drug-induced renal dysfunction, cortical damage and apoptosis. Moreover, TK reduced inflammatory cell accumulation in conjunction with diminished superoxide production and decreased expression of tumor necrosis factor-
, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1. The protective effects of TK were blocked by co-infusion of icatibant (1.3 µg h-1), indicating a kinin-B2 receptor-mediated signaling event. After cessation of gentamicin treatment, TK infusion for two weeks completely restored kidney histology and morphology comparable to that of saline-treated animals. Furthermore, TK reduced gentamicin-induced renal dysfunction and fibrosis as evidenced by decreased myofibroblast and collagen accumulation in the kidney. In vitro, gentamicin increased the number of apoptotic cells and caspase-3 activity, but decreased phosphorylation of the pro-survival kinase Akt, in immortalized rat proximal tubular cells; addition of TK and bradykinin prevented these effects. In conclusion, our findings indicate that kallikrein/kinin prevents and promotes recovery of gentamicin-induced renal injury by inhibiting apoptosis, inflammatory cell recruitment and fibrotic lesions through suppression of oxidative stress and pro-inflammatory mediator expression in animals during and after gentamicin treatment.
Key Words: aminoglycoside; apoptosis; fibrosis; inflammation; kidney.