NDT Advance Access originally published online on January 9, 2006
Nephrology Dialysis Transplantation 2006 21(3):624-633; doi:10.1093/ndt/gfi225
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Experimental Nephrology
Kallikrein/kinin protects against gentamicin-induced nephrotoxicity by inhibition of inflammation and apoptosis
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425-2211, USA
Correspondence and offprint requests to: Julie Chao, PhD, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA. Email: chaoj{at}musc.edu
Background. Our previous study showed that kallikrein gene transfer protects against gentamicin-induced nephrotoxicity and enhances renal function. In this study, we investigated the effects and potential mechanisms of kallikrein/kinin on inflammation and apoptosis induced by gentamicin.
Methods. Rats were injected subcutaneously with gentamicin daily for 10 days and received an intravenous injection of adenovirus carrying the human tissue kallikrein gene or control virus on the first day of gentamicin administration.
Results. After 10 days of gentamicin treatment, kallikrein gene transfer significantly attenuated gentamicin-induced tubular dilatation and lumenal protein casts. Moreover, kallikrein gene transfer reduced monocyte/macrophage infiltration, monocyte chemoattractant peptide-1 expression and renal cell apoptosis. Kallikrein's protective effects were accompanied by increased nitric oxide formation, and reduced NADH oxidase activity and superoxide production. Suppression of oxidative stress was associated with diminished c-jun N-terminal kinase activation and intercellular adhesion molecule-1 and transforming growth factor-ß protein levels. These biochemical effects were blocked by icatibant, indicating a kinin B2 receptor-mediated signalling event.
Conclusions. This study indicates that kallikrein/kinin protects against gentamicin-induced nephrotoxicity by inhibiting inflammatory cell recruitment and apoptosis through suppression of oxidative stress-mediated signalling pathways. These findings raise the potential of applying kallikrein therapy approaches in treating aminoglycoside-induced renal damage.
Keywords: apoptosis; gentamicin; inflammation; kidney; oxidative stress
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