Synchronized renal tubular cell death involves ferroptosis

Linkermann, Andreas, Skouta, Rachid, Himmerkus, Nina, Mulay, Shrikant R., Dewitz, Christin, De Zen, Federica, Prokai, Agnes, Zuchtriegel, Gabriele, Krombach, Fritz, Welz, Patrick-Simon, Weinlich, Ricardo, Vanden Berghe, Tom, Vandenabeele, Peter, Pasparakis, Manolis, Bleich, Markus, Weinberg, Joel M., Reichel, Christoph A., Braesen, Jan Hinrich, Kunzendorf, Ulrich, Anders, Hans-Joachim, Stockwell, Brent R., Green, Douglas R. and Krautwald, Stefan (2014) Synchronized renal tubular cell death involves ferroptosis Proceedings of the National Academy of Sciences of the United States of America, 111 (47). pp. 16836-16841.

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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.

Document Type: Article
Additional Information: Times Cited: 0 0
Research affiliation: Kiel University
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OceanRep > The Future Ocean - Cluster of Excellence
Refereed: Yes
ISSN: 0027-8424
Projects: Future Ocean
Date Deposited: 30 Mar 2015 12:32
Last Modified: 08 Mar 2017 10:18

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