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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 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.
Keywords
programmed cell death, regulated cell death, ferroptosis, necroptosis, apoptosis, ISCHEMIA-REPERFUSION INJURY, REGULATED NECROSIS, TNF-ALPHA, NECROPTOSIS, INFLAMMATION, CASPASE-8, MICE, FADD, INHIBITOR, PATHWAYS

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Citation

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Chicago
Linkermann, Andreas, Rachid Skouta, Nina Himmerkus, Sshrikant R Mulay, Christin Dewitz, Federica De Zen, Agnes Prokai, et al. 2014. “Synchronized Renal Tubular Cell Death Involves Ferroptosis.” Proceedings of the National Academy of Sciences of the United States of America 111 (47): 16836–16841.
APA
Linkermann, A., Skouta, R., Himmerkus, N., Mulay, S. R., Dewitz, C., De Zen, F., Prokai, A., et al. (2014). Synchronized renal tubular cell death involves ferroptosis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111(47), 16836–16841.
Vancouver
1.
Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, De Zen F, et al. Synchronized renal tubular cell death involves ferroptosis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2014;111(47):16836–41.
MLA
Linkermann, Andreas, Rachid Skouta, Nina Himmerkus, et al. “Synchronized Renal Tubular Cell Death Involves Ferroptosis.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 111.47 (2014): 16836–16841. Print.
@article{5819034,
  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 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.},
  author       = {Linkermann, Andreas and Skouta, Rachid and Himmerkus, Nina and Mulay, Sshrikant R and Dewitz, Christin and De Zen, Federica and Prokai, Agnes and Zuchtriegel, Gabriele and Krombach, Fritz and Welz, Patrick-Simon and Weinlich, Ricardo and Vanden Berghe, Tom and Vandenabeele, Peter and Pasparakis, Manolis and Bleich, Mark and Weinberg, Joel M and Reichel, Christoph A and Br{\"a}sen, Jan Hinrich and Kunzendorf, Ulrich and Anders, Hans-Joachim and Stockwell, Brent R and Green, Douglas R and Krautwald, Stefan},
  issn         = {0027-8424},
  journal      = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
  language     = {eng},
  number       = {47},
  pages        = {16836--16841},
  title        = {Synchronized renal tubular cell death involves ferroptosis},
  url          = {http://dx.doi.org/10.1073/pnas.1415518111},
  volume       = {111},
  year         = {2014},
}

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