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 (Gpx4cys/-) 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.
FörderungenSFB 1350 TP C2 transCampus initiative of S.R.B German Research Foundation (DFG) international research training group (IRTG) DFG German Federal Ministry of Education and Research (BMBF) VIP + program SPP2306 SFB-TRR 127 SFB-TRR 205 European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program Bavarian Ministry of Economic Affairs, Regional Development and Energy (StMWi) Else Kroner-Fresenius-Stiftung Ministry of Science and Higher Education of The Russian Federation Helmholtz Validation Fund Medical Clinic 3, University Hospital Carl Gustav Carus Dresden, Germany