|
Title
|
|
|
|
Synchronized renal tubular cell death involves ferroptosis
| |
|
Author
|
|
|
|
| |
|
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 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. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Proceedings of the National Academy of Sciences of the United States of America. - Washington, D.C.
| |
|
Publication
|
|
|
|
Washington, D.C.
:
2014
| |
|
ISSN
|
|
|
|
0027-8424
[Print]
1091-6490
[Online]
| |
|
DOI
|
|
|
|
10.1073/PNAS.1415518111
| |
|
Volume/pages
|
|
|
|
111
:47
(2014)
, p. 16836-16841
| |
|
ISI
|
|
|
|
000345662700050
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|