Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 47, Pages 16836-16841Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1415518111
Keywords
regulated cell death; programmed cell death; ferroptosis; necroptosis; apoptosis
Categories
Funding
- German Society for Nephrology
- Else Kroner-Fresenius Stiftung
- Pfizer
- Novartis
- Deutsche Forschungsgemeinschaft [AN372/9-2, AN371/12-2, AN372/15-1]
- New York State Stem Cell Science [C026715]
- US National Institutes of Health (NIH) [R01CA097061, R01GM085081, R01CA161061]
- Whitehall Foundation
- William Randolph Hearst Foundation
- Baby Alex Foundation
- NIH [R01DK34275]
- Veterans Administration
- Belgian grants (Interuniversity Attraction Poles Grants) [IAP 6/18, IAP 7/32]
- Flemish grants (Research Foundation Flanders) [FWO G.0875.11, FWO G.0973.11 N, FWO G.0A45.12 N, FWO G.0172.12, FWO G.0787.13N, G0C3114N, FWO KAN 31528711]
- Ghent University
- Flanders Institute for Biotechnology
- Flemish Government [BOF09/01M00709]
- Fresenius
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available