Journal
KIDNEY INTERNATIONAL
Volume 75, Issue 2, Pages 227-234Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2008.487
Keywords
acute kidney injury; cyclosporine nephrotoxicity; endothelial cells; transplantation; tubular epithelium
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Funding
- Fondo de Investigaciones Sanitarias [PI030888, PI061247, ISCIII-RETIC RedinREN 06/0016]
- Comunidad Autonoma de Madrid [GR/SAL/0418/2004, S-BIO-0283-2006 CIFRA]
- Sociedad Espanola de Nefrologia and Instituto Reina Sofia de Investigacion Nefrologica (IRSIN)
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Cyclosporin A is an immunosuppressant drug widely used in solid organ transplantation, but it has nephrotoxic properties that promote oxidative stress. The JAK2/STAT pathway has been implicated in both cell protection and cell injury; therefore, we determined a role of JAK2 in oxidative stress-mediated renal cell injury using pathophysiologically relevant oxidative challenges. The AG490 JAK2 inhibitor and overexpression of a dominant negative JAK2 protein protected endothelial and renal epithelial cells in culture against peroxide, superoxide anion and cyclosporin A induced cell death while reducing intracellular oxidation in cells challenged with peroxide and cyclosporin A. The decrease in Bcl2 expression and caspase 3 activation, induced by oxidative stress, was prevented by AG490. In mouse models of ischemia/reperfusion and cyclosporin A nephrotoxicity, AG490 decreased peritubular capillary and tubular cell injury. Our study shows that JAK2 inhibition is a promising renoprotective strategy defending endothelial and tubular cells from cyclosporin A-and oxidative stress- induced death.
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