Tonnus, Wulf ORCID: 0000-0002-9728-1413, Meyer, Claudia ORCID: 0000-0002-8722-0772, Steinebach, Christian ORCID: 0000-0001-5638-1955, Belavgeni, Alexia, von Maessenhausen, Anne, Gonzalez, Nadia Zamora, Maremonti, Francesca, Gembardt, Florian ORCID: 0000-0003-2739-345X, Himmerkus, Nina, Latk, Markus, Locke, Sophie, Marschner, Julian, Li, Wenjun, Short, Spencer, Doll, Sebastian ORCID: 0000-0002-8933-5362, 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, Guetschow, Michael, Conrad, Marcus ORCID: 0000-0003-1140-5612 and Linkermann, Andreas ORCID: 0000-0001-6287-9725 (2021). Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nat. Commun., 12 (1). BERLIN: NATURE RESEARCH. ISSN 2041-1723

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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 (Gpx4(cys/-)) 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. Necroptosis, a form of cell death, occurs in acute renal injury. Here, the authors show that ferroptosis-a form of cell death dependent on iron - also occurs during acute kidney injury, and show that an inhibitor of ferroptosis can improve survival in a mouse model of acute kidney damage.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Tonnus, WulfUNSPECIFIEDorcid.org/0000-0002-9728-1413UNSPECIFIED
Meyer, ClaudiaUNSPECIFIEDorcid.org/0000-0002-8722-0772UNSPECIFIED
Steinebach, ChristianUNSPECIFIEDorcid.org/0000-0001-5638-1955UNSPECIFIED
Belavgeni, AlexiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Maessenhausen, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez, Nadia ZamoraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maremonti, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gembardt, FlorianUNSPECIFIEDorcid.org/0000-0003-2739-345XUNSPECIFIED
Himmerkus, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Latk, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Locke, SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marschner, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, WenjunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Short, SpencerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doll, SebastianUNSPECIFIEDorcid.org/0000-0002-8933-5362UNSPECIFIED
Ingold, IrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Proneth, BettinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daniel, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kabgani, NazaninUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kramann, RafaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motika, StephenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hergenrother, Paul J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bornstein, Stefan R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hugo, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, Jan UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amann, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anders, Hans-JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreisel, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pratt, DerekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guetschow, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Conrad, MarcusUNSPECIFIEDorcid.org/0000-0003-1140-5612UNSPECIFIED
Linkermann, AndreasUNSPECIFIEDorcid.org/0000-0001-6287-9725UNSPECIFIED
URN: urn:nbn:de:hbz:38-604671
DOI: 10.1038/s41467-021-24712-6
Journal or Publication Title: Nat. Commun.
Volume: 12
Number: 1
Date: 2021
Publisher: NATURE RESEARCH
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL-DEATH; NECROPTOSIS; MLKL; GPX4; GENERATION; CLEARANCE; MECHANISM; PATHWAYSMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60467

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