Synchronized renal tubular cell death involves ferroptosis
Synchronized renal tubular cell death involves ferroptosis
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DOI：
10.1073/pnas.1415518111
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发表时间：
2014-11-25
影响因子：
11.1
通讯作者：
Krautwald, Stefan
中科院分区：
文献类型：
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作者：
Linkermann, Andreas;Skouta, Rachid;Krautwald, Stefan
受体相互作用蛋白激酶3（RIPK 3）介导的坏死性凋亡被认为是导致缺血再灌注损伤（IRI）中实质细胞调节性坏死的病理生理学主要途径，并且已知Fas相关死亡结构域蛋白（FADD）或半胱天冬酶-8的缺失使组织敏感而经历自发性坏死性凋亡。在这里，我们证明，肾小管不经历致敏后，无论是FADD或caspase-8的基因消融坏死性凋亡和RIPK 1抑制剂necrostatin-1（Nec-1）不保护新鲜分离的肾小管缺氧损伤。相反，铁依赖性铁凋亡直接导致肾小管同步坏死，如IRI和草酸盐晶体诱导的急性肾损伤模型的活体显微镜所示。为了在体内抑制铁凋亡，我们产生了一种新的第三代ferrostatin（称为16-86），我们证明它比第一类化合物ferrostatin-1（Fer-1）更稳定，对代谢和血浆更有效。即使在非常严重的IRI条件下，16-86也发挥了强保护作用，其程度是以前在任何鼠环境中都不允许存活的。此外，16-86进一步增强了通过与坏死抑制素和抑制线粒体通透性转换的化合物的组合疗法介导的对IRI的强保护作用。因此，肾小管代表一种不会因FADD或半胱天冬酶-8的丢失而对坏死性凋亡敏感的组织。最后，铁凋亡介导缺血后和中毒性肾坏死，这可能是治疗靶点的铁抑制素和联合治疗。
Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia-reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, iron-dependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury. To suppress ferroptosis in vivo, we generated a novel third-generation ferrostatin (termed 16-86), which we demonstrate to be more stable, to metabolism and plasma, and more potent, compared with the firstin-class compound ferrostatin-1 (Fer-1). Even in conditions with extraordinarily severe IRI, 16-86 exerts strong protection to an extent which has not previously allowed survival in any murine setting. In addition, 16-86 further potentiates the strong protective effect on IRI mediated by combination therapy with necrostatins and compounds that inhibit mitochondrial permeability transition. Renal tubules thus represent a tissue that is not sensitized to necroptosis by loss of FADD or caspase-8. Finally, ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins and by combination therapy.