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dc.contributor.author Linkermann A
dc.contributor.author Skouta R
dc.contributor.author Himmerkus N
dc.contributor.author Mulay SR
dc.contributor.author Dewitz C
dc.contributor.author De Zen F
dc.contributor.author Prókai, Ágnes
dc.contributor.author Zuchtriegel G
dc.contributor.author Krombach F
dc.contributor.author Welz P-S
dc.contributor.author Weinlich R
dc.contributor.author Berghe TV
dc.contributor.author Vandenabeele P
dc.contributor.author Pasparakis M
dc.contributor.author Bleich M
dc.contributor.author Weinberg JM
dc.contributor.author Reichel CA
dc.contributor.author Bräsen JH
dc.contributor.author Kunzendorf U
dc.contributor.author Anders H-J
dc.contributor.author Stockwell BR
dc.contributor.author Green DR
dc.contributor.author Krautwald S
dc.date.accessioned 2015-02-25T08:44:57Z
dc.date.available 2015-02-25T08:44:57Z
dc.date.issued 2014
dc.identifier 84913582286
dc.identifier.citation pagination=16836-16841; journalVolume=111; journalIssueNumber=47; journalTitle=PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA;
dc.identifier.uri http://repo.lib.semmelweis.hu//handle/123456789/1167
dc.identifier.uri doi:10.1073/pnas.1415518111
dc.description.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, irondependent 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.
dc.relation.ispartof urn:issn:0027-8424
dc.title Synchronized renal tubular cell death involves ferroptosis
dc.type Journal Article
dc.date.updated 2015-01-21T10:27:36Z
dc.language.rfc3066 en
dc.identifier.mtmt 2813605
dc.contributor.department SE/AOK/K/I. Sz. Gyermekgyógyászati Klinika
dc.contributor.institution Semmelweis Egyetem
dc.mtmt.swordnote N1 Funding Details: AN371/12-2, DFG, Whitehall Foundation N1 Funding Details: AN372/15-1, DFG, Whitehall Foundation N1 Funding Details: AN372/9-2, DFG, Whitehall Foundation N1 Funding Details: R01CA097061, NIH, Whitehall Foundation N1 Funding Details: R01CA161061, NIH, Whitehall Foundation N1 Funding Details: R01GM085081, NIH, Whitehall Foundation N1 Funding Details: Whitehall Foundation N1 Funding Details: R01DK34275, NIH, Whitehall Foundation


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