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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)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cell-death; Necroptosis; Mlkl; Gpx4; Generation; Clearance; Mechanism; Pathways
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 12, Heft: 1, Seiten: , Artikelnummer: 4402 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
Institute for Pancreatic Beta Cell Research (IPI)
Förderungen 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