Details

Autor(en) / Beteiligte

• 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
• Berghe, Tom Vanden
• 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
• Dixit, Vishva M.

Titel

Synchronized renal tubular cell death involves ferroptosis

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2014-11, Vol.111 (47), p.16836-16841

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2014

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Significance Cell death by regulated necrosis causes tremendous tissue damage in a wide variety of diseases, including myocardial infarction, stroke, sepsis, and ischemia–reperfusion injury upon solid organ transplantation. Here, we demonstrate that an iron-dependent form of regulated necrosis, referred to as ferroptosis, mediates regulated necrosis and synchronized death of functional units in diverse organs upon ischemia and other stimuli, thereby triggering a detrimental immune response. We developed a novel third-generation inhibitor of ferroptosis that is the first compound in this class that is stable in plasma and liver microsomes and that demonstrates high efficacy when supplied alone or in combination therapy. 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.