Par-4 is a novel mediator of renal tubule cell death in models of ischemia-reperfusion injury.
Par-4 is a novel mediator of renal tubule cell death in models of ischemia-reperfusion injury.
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DOI：
10.1152/ajprenal.00083.2006
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Jun Xie;Q. Guo
中科院分区：
文献类型：
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作者：
Jun Xie;Q. Guo
前列腺细胞凋亡反应 4 (Par-4) 是一种亮氨酸拉链蛋白，与前列腺癌和神经元组织中的细胞凋亡相关。 Par-4 (Leu.zip) 的亮氨酸拉链结构域介导蛋白质-蛋白质相互作用，这对于细胞凋亡敏感至关重要，而 Leu.zip 的过度表达会以显性负性方式阻断 Par-4 活性。缺血再灌注诱导的肾损伤（IRI）在临床上具有重要意义，因为它通常会损害肾小管上皮细胞和肾小球细胞，并且是急性肾衰竭（ARF）的最常见原因。我们现在报道 Par-4 在肾小管细胞中表达，并且 Par-4 活性的异常表达在充分表征的肾 IRI 模型中激活凋亡途径中起着至关重要的作用。在体外 HK-2 细胞中化学缺血再灌注后观察到 Par-4 水平升高，在体内双侧夹紧肾蒂后观察到小鼠肾小管细胞中 Par-4 水平升高。特异性par-4反义寡核苷酸对Par-4表达的抑制很大程度上阻止了IRI诱导的HK-2细胞凋亡。这些细胞中 Par-4 的过度表达加剧了线粒体功能障碍和 caspase 激活，并增加了对 IRI 诱导的细胞凋亡的敏感性。 Par-4 的显性负调节因子 Leu.zip 的表达在很大程度上防止了线粒体功能障碍和 caspase 激活，并显着抑制了 HK-2 细胞中 IRI 诱导的细胞凋亡。此外，延长 IRI 后，Par-4 的转染增加，而 Leu.zip 的转染减少 HK-2 细胞的坏死。这些结果表明 Par-4 是 IRI 后肾小管细胞损伤的新型早期介质，并为开发肾 IRI 和 ARF 的新治疗策略提供了潜在靶点。
Prostate apoptosis response-4 (Par-4) is a leucine zipper protein linked to apoptotic cell death in prostate cancer and neuronal tissues. The leucine zipper domain of Par-4 (Leu.zip) mediates protein-protein interactions that are essential for sensitization of cells to apoptosis, and overexpression of Leu.zip blocks Par-4 activity in a dominant negative fashion. Ischemia-reperfusion-induced renal injury (IRI) is clinically important because it typically damages renal tubular epithelial cells and glomerular cells, and it is the most common cause of acute renal failure (ARF). We now report that Par-4 is expressed in renal tubule cells and that aberrant expression of Par-4 activity plays a crucial role in activating apoptotic pathways in well-characterized models of renal IRI. Increased levels of Par-4 were observed following chemical ischemia-reperfusion in HK-2 cells in vitro and in mouse renal tubular cells following bilateral clamping of renal pedicles in vivo. Inhibition of Par-4 expression by specific par-4 antisense oligonucleotides largely prevented HK-2 cell apoptosis induced by IRI. Overexpression of Par-4 in these cells exacerbated mitochondrial dysfunction and caspase activation and conferred increased sensitivity to IRI-induced apoptosis. Expression of Leu.zip, a dominant negative regulator of Par-4, largely prevented mitochondrial dysfunction and caspase activation and significantly inhibited IRI-induced apoptosis in HK-2 cells. In addition, transfection of Par-4 increased while transfection of Leu.zip decreased necrosis in HK-2 cells following prolonged IRI. These results identify Par-4 as a novel and early mediator of renal tubule cell injury following IRI and provide a potential target for developing new therapeutic strategies for renal IRI and ARF.