表观遗传修饰物通过诱导 p66shc 发挥肾毒性作用。
Epigenetic modifiers exert renal toxicity through induction of p66shc.
机构信息
Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, MS, U.S.A.
出版信息
Anticancer Res. 2011 Oct;31(10):3267-71.
BACKGROUND/AIMS: Trichostatin A (TSA) and 5-azacytidine (5AZA) induce reactive oxygen species (ROS)-mediated injury in renal proximal tubule cells. Since TSA and 5AZA are activators of p66shc, we questioned whether p66shc may mediate renal toxicity of TSA- and 5AZA.
MATERIALS AND METHODS
Renal proximal tubule cells were treated with either TSA or 5AZA for 24 hours followed by treatment with 200 μM H(2)O(2). Expression of p66shc and activity of its promoter, as well as its mitochondrial and cytochrome c binding were determined. Impact of knockdown of p66shc and mutation of its cytochrome c-binding site on ROS production and cell injury was studied.
RESULTS
TSA, and 5AZA increased expression of p66shc through induction of its promoter and also increased its mitochondrial/cytochrome c binding. Knockdown or mutation of the cytochrome c binding site of p66shc attenuated ROS production and cell injury.
CONCLUSION
Therapeutic means that interfere with induction of p66shc may ameliorate renal toxicity of those epigenetic modifiers.
背景/目的：曲古抑菌素 A（TSA）和 5-氮杂胞苷（5AZA）诱导肾近端小管细胞产生活性氧（ROS）介导的损伤。由于 TSA 和 5AZA 是 p66shc 的激活剂，我们质疑 p66shc 是否可能介导 TSA 和 5AZA 的肾毒性。
材料和方法
肾近端小管细胞用 TSA 或 5AZA 处理 24 小时，然后用 200μM H（2）O（2）处理。测定 p66shc 的表达及其启动子的活性，以及其线粒体和细胞色素 c 结合。研究 p66shc 的敲低和其细胞色素 c 结合位点突变对 ROS 产生和细胞损伤的影响。
结果
TSA 和 5AZA 通过诱导其启动子增加了 p66shc 的表达，同时增加了其线粒体/细胞色素 c 结合。p66shc 的细胞色素 c 结合位点的敲低或突变减弱了 ROS 产生和细胞损伤。
结论
干扰 p66shc 诱导的治疗方法可能改善这些表观遗传修饰剂的肾毒性。
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