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 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 Kramann, Stephen 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 and Andreas Linkermann ()
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Wulf Tonnus: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Claudia Meyer: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Christian Steinebach: University of Bonn
Alexia Belavgeni: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Anne Mässenhausen: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Nadia Zamora Gonzalez: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Francesca Maremonti: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Florian Gembardt: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Nina Himmerkus: Christian-Albrecht-University Kiel
Markus Latk: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Sophie Locke: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Julian Marschner: University Hospital LMU Munich
Wenjun Li: Washington University
Spencer Short: University of Ottawa
Sebastian Doll: Helmholtz Zentrum München
Irina Ingold: Helmholtz Zentrum München
Bettina Proneth: Helmholtz Zentrum München
Christoph Daniel: Friedrich-Alexander University (FAU) Erlangen-Nürnberg
Nazanin Kabgani: Rheumatological and Immunological Disease, University Hospital of the RWTH Aachen
Rafael Kramann: Rheumatological and Immunological Disease, University Hospital of the RWTH Aachen
Stephen Motika: University of Illinois
Paul J. Hergenrother: University of Illinois
Stefan R. Bornstein: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Christian Hugo: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Jan Ulrich Becker: University Hospital of Cologne
Kerstin Amann: Friedrich-Alexander University (FAU) Erlangen-Nürnberg
Hans-Joachim Anders: University Hospital LMU Munich
Daniel Kreisel: Washington University
Derek Pratt: University of Ottawa
Michael Gütschow: University of Bonn
Marcus Conrad: Helmholtz Zentrum München
Andreas Linkermann: University Hospital Carl Gustav Carus at the Technische Universität Dresden

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24712-6

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DOI: 10.1038/s41467-021-24712-6

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