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Synchronized renal tubular cell death involves ferroptosis.

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.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Linkermann A,Skouta R,Himmerkus N,Mulay SR,Dewitz C,De Zen F,Prokai A,Zuchtriegel G,Krombach F,Welz PS,Weinlich R,Vanden Berghe T,Vandenabeele P,Pasparakis M,Bleich M,Weinberg JM,Reichel CA,Bräsen JH,Kunzendorf U,An

doi

10.1073/pnas.1415518111

subject

Has Abstract

pub_date

2014-11-25 00:00:00

pages

16836-41

issue

eissn

0027-8424

issn

1091-6490

pii

1415518111

journal_volume

111

pub_type

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Synchronized renal tubular cell death involves ferroptosis.