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Tonnus, W.* ; Meyer, C.* ; Steinebach, C.* ; Belavgeni, A.* ; von Mässenhausen, A.* ; Gonzalez, N.Z.* ; Maremonti, F.* ; Gembardt, F.* ; Himmerkus, N.* ; Latk, M.* ; Locke, S.* ; Marschner, J.A.* ; Li, W.* ; Short, S.C.* ; Doll, S. ; Ingold, I. ; Proneth, B. ; Daniel, C.* ; Kabgani, N.* ; Kramann, R.* ; Motika, S.* ; Hergenrother, P.J.* ; Bornstein, S.R. ; Hugo, C.* ; Becker, J.U.* ; Amann, K.* ; Anders, H.J.* ; Kreisel, D.* ; Pratt, D.A.* ; Gütschow, M.* ; Conrad, M. ; Linkermann, A.*

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

Nat. Commun. 12:4402 (2021)
Publ. Version/Full Text DOI PMC
Open Access Gold
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cell-death; Necroptosis; Mlkl; Gpx4; Generation; Clearance; Mechanism; Pathways
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 12, Issue: 1, Pages: , Article Number: 4402 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Metabolism and Cell Death (MCD)
Institute of Pancreatic Islet Research (IPI)
POF-Topic(s) 30203 - Molecular Targets and Therapies
90000 - German Center for Diabetes Research
Research field(s) Genetics and Epidemiology
Helmholtz Diabetes Center
PSP Element(s) G-506900-001
G-502600-007
Grants SFB 1350 TP C2
transCampus initiative of S.R.B
German Research Foundation (DFG)
international research training group (IRTG)
DFG
German Federal Ministry of Education and Research (BMBF) VIP + program
SPP2306
SFB-TRR 127
SFB-TRR 205
European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program
Bavarian Ministry of Economic Affairs, Regional Development and Energy (StMWi)
Else Kroner-Fresenius-Stiftung
Ministry of Science and Higher Education of The Russian Federation
Helmholtz Validation Fund
Medical Clinic 3, University Hospital Carl Gustav Carus Dresden, Germany
DOI 10.1038/s41467-021-24712-6
WOS ID WOS:000677640700011
Scopus ID 85111097567
PubMed ID 34285231
Erfassungsdatum 2021-08-06
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