Neria Fernando, Castilla Maria A, Sanchez Ruth Fernandez, Gonzalez Pacheco Francisco R, Deudero Juan J P, Calabia Olalla, Tejedor Alberto, Manzarbeitia Felix, Ortiz Alberto, Caramelo Carlos
Laboratorio de Nefrologia-Hipertension, Fundacion Jimenez Diaz-Capio, Universidad Autonoma, Madrid, Spain.
Kidney Int. 2009 Jan;75(2):227-34. doi: 10.1038/ki.2008.487. Epub 2008 Sep 24.
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.
环孢素A是一种广泛用于实体器官移植的免疫抑制剂，但它具有促进氧化应激的肾毒性特性。JAK2/STAT信号通路与细胞保护和细胞损伤均有关联；因此，我们利用病理生理学相关的氧化应激刺激，确定了JAK2在氧化应激介导的肾细胞损伤中的作用。AG490 JAK2抑制剂和显性负性JAK2蛋白的过表达可保护培养中的内皮细胞和肾上皮细胞免受过氧化氢、超氧阴离子和环孢素A诱导的细胞死亡，同时减少用过氧化氢和环孢素A刺激的细胞内氧化。AG490可防止氧化应激诱导的Bcl2表达降低和半胱天冬酶3激活。在缺血/再灌注和环孢素A肾毒性的小鼠模型中，AG490可减轻肾小管周围毛细血管和肾小管细胞损伤。我们的研究表明，抑制JAK2是一种有前景的肾脏保护策略，可保护内皮细胞和肾小管细胞免受环孢素A和氧化应激诱导的死亡。
