Rip1 (Receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury
Rip1 (Receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury
复制标题
DOI：
10.1038/ki.2011.450
复制
发表时间：
2012-04-01
影响因子：
19.6
通讯作者：
Krautwald, Stefan
中科院分区：
文献类型：
--
作者：
Linkermann, Andreas;Braesen, Jan H.;Krautwald, Stefan
肾缺血/再灌注损伤中的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）的作用尚未得到评价。在这里，我们确定了死亡受体介导的，但在小鼠肾小管细胞的caspase-独立的细胞死亡的存在，并通过添加necrostatin-1，一个高度特异性的受体相互作用的蛋白激酶1抑制剂，其特征在于坏死性凋亡。受体相互作用蛋白激酶1和3的检测在全肾裂解液和新鲜分离的小鼠近端小管导致我们调查的贡献，坏死性凋亡在小鼠模型的肾缺血/再灌注损伤。用坏死抑素-1治疗减少了器官损伤和肾衰竭，即使在再灌注后给药，在致死性肾缺血/再灌注损伤模型中导致显著的生存益处。出乎意料的是，pan-半胱天冬酶抑制剂zVAD对细胞凋亡的特异性阻断并不能防止肾缺血/再灌注损伤中的器官损伤或体内尿素和肌酐的增加。因此，坏死性凋亡是存在的，在缺血性肾损伤的病理生理过程中具有功能相关性，并且在这种情况下显示出坏死性凋亡相对于细胞凋亡的优势。Necrostatin-1可能具有预防和治疗肾缺血/再灌注损伤的治疗潜力。Kidney International（2012）81，751-761; doi：10.1038/ki.2011.450; 2012年1月11日在线发表
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. Kidney International (2012) 81, 751-761; doi:10.1038/ki.2011.450; published online 11 January 2012