Linkermann, Andreas ORCID: 0000-0001-6287-9725, Skouta, Rachid ORCID: 0000-0003-3324-4362, Himmerkus, Nina ORCID: 0000-0002-2910-6728, Mulay, Shrikant R., Dewitz, Christin, De Zen, Federica, Prokai, Agnes, Zuchtriegel, Gabriele, Krombach, Fritz, Welz, Patrick-Simon ORCID: 0000-0001-8370-625X, Weinlich, Ricardo ORCID: 0000-0001-6822-7330, Vanden Berghe, Tom, Vandenabeele, Peter ORCID: 0000-0002-6669-8822, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Bleich, Markus ORCID: 0000-0002-1745-2295, Weinberg, Joel M., Reichel, Christoph A., Braesen, Jan Hinrich, Kunzendorf, Ulrich, Anders, Hans-Joachim ORCID: 0000-0003-2434-2956, Stockwell, Brent R., Green, Douglas R. and Krautwald, Stefan (2014). Synchronized renal tubular cell death involves ferroptosis. Proc. Natl. Acad. Sci. U. S. A., 111 (47). S. 16836 - 16842. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia-reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, iron-dependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury. To suppress ferroptosis in vivo, we generated a novel third-generation ferrostatin (termed 16-86), which we demonstrate to be more stable, to metabolism and plasma, and more potent, compared with the firstin-class compound ferrostatin-1 (Fer-1). Even in conditions with extraordinarily severe IRI, 16-86 exerts strong protection to an extent which has not previously allowed survival in any murine setting. In addition, 16-86 further potentiates the strong protective effect on IRI mediated by combination therapy with necrostatins and compounds that inhibit mitochondrial permeability transition. Renal tubules thus represent a tissue that is not sensitized to necroptosis by loss of FADD or caspase-8. Finally, ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins and by combination therapy.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Linkermann, AndreasUNSPECIFIEDorcid.org/0000-0001-6287-9725UNSPECIFIED
Skouta, RachidUNSPECIFIEDorcid.org/0000-0003-3324-4362UNSPECIFIED
Himmerkus, NinaUNSPECIFIEDorcid.org/0000-0002-2910-6728UNSPECIFIED
Mulay, Shrikant R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dewitz, ChristinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Zen, FedericaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prokai, AgnesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zuchtriegel, GabrieleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krombach, FritzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Welz, Patrick-SimonUNSPECIFIEDorcid.org/0000-0001-8370-625XUNSPECIFIED
Weinlich, RicardoUNSPECIFIEDorcid.org/0000-0001-6822-7330UNSPECIFIED
Vanden Berghe, TomUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vandenabeele, PeterUNSPECIFIEDorcid.org/0000-0002-6669-8822UNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
Bleich, MarkusUNSPECIFIEDorcid.org/0000-0002-1745-2295UNSPECIFIED
Weinberg, Joel M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reichel, Christoph A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braesen, Jan HinrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kunzendorf, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anders, Hans-JoachimUNSPECIFIEDorcid.org/0000-0003-2434-2956UNSPECIFIED
Stockwell, Brent R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Green, Douglas R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krautwald, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-423028
DOI: 10.1073/pnas.1415518111
Journal or Publication Title: Proc. Natl. Acad. Sci. U. S. A.
Volume: 111
Number: 47
Page Range: S. 16836 - 16842
Date: 2014
Publisher: NATL ACAD SCIENCES
Place of Publication: WASHINGTON
ISSN: 0027-8424
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ISCHEMIA-REPERFUSION INJURY; REGULATED NECROSIS; TNF-ALPHA; NECROPTOSIS; INFLAMMATION; CASPASE-8; PATHWAYS; MICE; FADD; INHIBITORMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/42302

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