Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany.
Kidney Int. 2012 Apr;81(8):751-61. doi: 10.1038/ki.2011.450. Epub 2012 Jan 11.
Loss of kidney function in renal ischemia/reperfusion injury is due to programmed cell death, but the contribution of necroptosis, a newly discovered form of programmed necrosis, has not been evaluated. Here, we identified the presence of death receptor-mediated but caspase-independent cell death in murine tubular cells and characterized it as necroptosis by the addition of necrostatin-1, a highly specific receptor-interacting protein kinase 1 inhibitor. The detection of receptor-interacting protein kinase 1 and 3 in whole-kidney lysates and freshly isolated murine proximal tubules led us to investigate the contribution of necroptosis in a mouse model of renal ischemia/reperfusion injury. Treatment with necrostatin-1 reduced organ damage and renal failure, even when administered after reperfusion, resulting in a significant survival benefit in a model of lethal renal ischemia/reperfusion injury. Unexpectedly, specific blockade of apoptosis by zVAD, a pan-caspase inhibitor, did not prevent the organ damage or the increase in urea and creatinine in vivo in renal ischemia/reperfusion injury. Thus, necroptosis is present and has functional relevance in the pathophysiological course of ischemic kidney injury and shows the predominance of necroptosis over apoptosis in this setting. Necrostatin-1 may have therapeutic potential to prevent and treat renal ischemia/reperfusion injury.
肾缺血/再灌注损伤导致肾功能丧失是由于程序性细胞死亡，但坏死性凋亡（一种新发现的程序性坏死形式）的作用尚未得到评估。在这里，我们在鼠肾小管细胞中发现了死亡受体介导但半胱天冬酶非依赖性细胞死亡，并通过添加高度特异性受体相互作用蛋白激酶 1 抑制剂 necrostatin-1 将其特征化为坏死性凋亡。在全肾裂解物和新鲜分离的鼠近端肾小管中检测到受体相互作用蛋白激酶 1 和 3，促使我们在鼠肾缺血/再灌注损伤模型中研究坏死性凋亡的作用。用 necrostatin-1 治疗可减轻器官损伤和肾衰竭，即使在再灌注后给予，在致死性肾缺血/再灌注损伤模型中可显著提高生存率。出乎意料的是，凋亡的特异性阻断（通过 pan-caspase 抑制剂 zVAD）并不能预防肾缺血/再灌注损伤中的器官损伤或体内尿素和肌酐的增加。因此，坏死性凋亡在缺血性肾损伤的病理生理过程中存在且具有功能相关性，并显示在这种情况下坏死性凋亡比凋亡更为突出。Necrostatin-1 可能具有预防和治疗肾缺血/再灌注损伤的治疗潜力。
