Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury

Wulf Tonnus, Claudia Meyer, Christian Steinebach, Alexia Belavgeni, Anne von Mässenhausen, Nadia Zamora Gonzalez, Francesca Maremonti, Florian Gembardt, Nina Himmerkus, Markus Latk, Sophie Locke, Julian Marschner, Wenjun Li, Spencer Short, Sebastian Doll, Irina Ingold, Bettina Proneth, Christoph Daniel, Nazanin Kabgani, Rafael KramannStephen Motika, Paul J. Hergenrother, Stefan R. Bornstein, Christian Hugo, Jan Ulrich Becker, Kerstin Amann, Hans Joachim Anders, Daniel Kreisel, Derek Pratt, Michael Gütschow, Marcus Conrad, Andreas Linkermann*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article number4402
JournalNature Communications
Issue number1
Publication statusPublished - 20 Jul 2021

Bibliographical note

Funding Information:
We would like to cordially thank Cemile Jakupoglu and Markus Brielmeier for help in generating the Fsp1−/−-mice, Romy Opitz for expert technical assistance, and Renata Drtina for critically reading the manuscript. We thank the histology facility, the FACS facility, as well as the light microscopy facility at the CMCB Dresden, in particular Hella Hartmann, for the expert help. Work in the Linkermann Lab is funded by the Medical Clinic 3, University Hospital Carl Gustav Carus Dresden, Germany, and supported by the SFB-TRR 205, SFB-TRR 127, SPP2306, and the international research training group (IRTG) 2251. This work was supported by the German Research Foundation (DFG) (Heisenberg-Professorship to A.L. (project number 324141047), GE2845/1-1 to F.G., AN372/24-1 to H.J.A. and KR3363/3-1 to N.K.). We received further funding for this project from the transCampus initiative of S.R.B. Work in the Conrad Lab is funded by the DFG (CO 291/5-2; CO 291/7-1; PR 1752/3-1), the German Federal Ministry of Education and Research (BMBF) VIP + program 03VP04260, the Helmholtz Validation Fund (0042), the Ministry of Science and Higher Education of the Russian Federation (075-15-2019-1933), the Else Kröner-Fresenius-Stiftung, the Bavarian Ministry of Economic Affairs, Regional Development and Energy (StMWi), and M.C. has further received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. GA 884754). K.A. and C.D. received funding by the SFB 1350 TP C2.

Publisher Copyright:
© 2021, The Author(s).


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