Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
Biotechnology Center, Technische Universität Dresden, Dresden, Germany.
Nat Commun. 2021 Jul 20;12(1):4402. doi: 10.1038/s41467-021-24712-6.
Acute kidney injury (AKI) is morphologically characterized by a synchronized plasma membrane rupture of cells in a specific section of a nephron, referred to as acute tubular necrosis (ATN). Whereas the involvement of necroptosis is well characterized, genetic evidence supporting the contribution of ferroptosis is lacking. Here, we demonstrate that the loss of ferroptosis suppressor protein 1 (Fsp1) or the targeted manipulation of the active center of the selenoprotein glutathione peroxidase 4 (Gpx4) sensitize kidneys to tubular ferroptosis, resulting in a unique morphological pattern of tubular necrosis. Given the unmet medical need to clinically inhibit AKI, we generated a combined small molecule inhibitor (Nec-1f) that simultaneously targets receptor interacting protein kinase 1 (RIPK1) and ferroptosis in cell lines, in freshly isolated primary kidney tubules and in mouse models of cardiac transplantation and of AKI and improved survival in models of ischemia-reperfusion injury. Based on genetic and pharmacological evidence, we conclude that GPX4 dysfunction hypersensitizes mice to ATN during AKI. Additionally, we introduce Nec-1f, a solid inhibitor of RIPK1 and weak inhibitor of ferroptosis.
急性肾损伤 (AKI) 在形态学上的特征是特定肾单位区段的细胞同步发生质膜破裂，即急性肾小管坏死 (ATN)。尽管细胞坏死已得到充分研究，但缺乏支持铁死亡参与的遗传证据。在这里，我们证明铁死亡抑制蛋白 1 (Fsp1) 的缺失或硒蛋白谷胱甘肽过氧化物酶 4 (Gpx4) 活性中心的靶向操作会使肾脏对肾小管铁死亡敏感，导致肾小管坏死的独特形态模式。鉴于临床上抑制 AKI 的医疗需求尚未得到满足，我们开发了一种联合小分子抑制剂 (Nec-1f)，它可以同时靶向受体相互作用蛋白激酶 1 (RIPK1) 和细胞系、新鲜分离的原代肾小管以及心脏移植和 AKI 小鼠模型中的铁死亡，并提高了缺血再灌注损伤模型的存活率。基于遗传和药理学证据，我们得出结论，GPX4 功能障碍使小鼠在 AKI 期间对 ATN 更加敏感。此外，我们引入了 Nec-1f，它是 RIPK1 的有效抑制剂和铁死亡的弱抑制剂。
