Inhibition of JAK2 protects renal endothelial and epithelial cells from oxidative stress and cyclosporin A toxicity.
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.
Neria
Fernando
F
Laboratorio de Nefrologia-Hipertension, Fundacion Jimenez Diaz-Capio, Universidad Autonoma, Madrid, Spain. fneria@fjd.es
Castilla
Maria A
MA
Sanchez
Ruth Fernandez
RF
Gonzalez Pacheco
Francisco R
FR
Deudero
Juan J P
JJ
Calabia
Olalla
O
Tejedor
Alberto
A
Manzarbeitia
Felix
F
Ortiz
Alberto
A
Caramelo
Carlos
C
D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D007668:Kidney / Q000166:cytology*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D020011:Protective Agents / Q000494:pharmacology; D015427:Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control; D020032:Tyrphostins / Q000494:pharmacology*
D020011:Protective Agents; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D016572:Cyclosporine; D053614:Janus Kinase 2