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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number4402
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint

Dive into the research topics of 'Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury'. Together they form a unique fingerprint.

Cite this