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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., Bräsen, Jan Hinrich, Kunzendorf, Ulrich, Anders, Hans-Joachim, Stockwell, Brent R., Green, Douglas R., Krautwald, Stefan
- Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.47 pp. 16836-16841
- death, immune response, liver microsomes, myocardial infarction, necrosis, organ transplantation, sepsis (infection), stroke
- 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 first-in-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.