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

• Published in: Nature communications Vol. 12; no. 1; pp. 4402 - 14
• Main Authors: Tonnus, Wulf, Meyer, Claudia, Steinebach, Christian, Belavgeni, Alexia, von Mässenhausen, Anne, Gonzalez, Nadia Zamora, Maremonti, Francesca, Gembardt, Florian, Himmerkus, Nina, Latk, Markus, Locke, Sophie, Marschner, Julian, Li, Wenjun, Short, Spencer, Doll, Sebastian, Ingold, Irina, Proneth, Bettina, Daniel, Christoph, Kabgani, Nazanin, Kramann, Rafael, Motika, Stephen, Hergenrother, Paul J, Bornstein, Stefan R, Hugo, Christian, Becker, Jan Ulrich, Amann, Kerstin, Anders, Hans-Joachim, Kreisel, Daniel, Pratt, Derek, Gütschow, Michael, Conrad, Marcus, Linkermann, Andreas
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 20.07.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - etiology; Acute Kidney Injury - pathology; Animal models; Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Cell death; Cell lines; Cisplatin - administration & dosage; Cisplatin - toxicity; Disease Models, Animal; Epithelial Cells; Female; Ferroptosis; Ferroptosis - drug effects; Ferroptosis - physiology; Gene Knockdown Techniques; Glutathione; Glutathione peroxidase; Heart transplantation; Heart Transplantation - adverse effects; Heart transplants; HT29 Cells; Humans; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazoles - therapeutic use; Indoles - chemistry; Indoles - pharmacology; Indoles - therapeutic use; Injuries; Ischemia; Kidney Tubules - pathology; Kidneys; Kinases; Male; Mice; Mice, Transgenic; Microsomes, Liver; Mitochondrial Proteins - metabolism; Necroptosis; Necrosis; Necrosis - drug therapy; Necrosis - etiology; Necrosis - pathology; NIH 3T3 Cells; Oxidoreductases - genetics; Oxidoreductases - metabolism; Peroxidase; Phospholipid Hydroperoxide Glutathione Peroxidase - antagonists & inhibitors; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Primary Cell Culture; Protein kinase; Proteins; Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Reperfusion; Reperfusion Injury - drug therapy; Reperfusion Injury - etiology; Reperfusion Injury - pathology; Survival; Transplantation; Tubules
• ISSN: 2041-1723; 2041-1723
• 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.