Sex differences in resilience to ferroptosis underlie sexual dimorphism in kidney injury and repair.

Humans Female Male Mice Animals Ferroptosis Sex Characteristics NF-E2-Related Factor 2 / genetics Kidney / metabolism Acute Kidney Injury
CP: Molecular biology GPX4 NRF2 acute kidney injury cell fate cellular plasticity ferroptosis glutathione Peroxidase 4 kidney injury and repair sexual dimorphism single-cell transcriptomics

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
08 11 2022
Historique:
received: 04 04 2022
revised: 27 08 2022
accepted: 14 10 2022
entrez: 9 11 2022
pubmed: 10 11 2022
medline: 15 11 2022
Statut: ppublish

Résumé

In both humans and mice, repair of acute kidney injury is worse in males than in females. Here, we provide evidence that this sexual dimorphism results from sex differences in ferroptosis, an iron-dependent, lipid-peroxidation-driven regulated cell death. Using genetic and single-cell transcriptomic approaches in mice, we report that female sex confers striking protection against ferroptosis, which was experimentally induced in proximal tubular (PT) cells by deleting glutathione peroxidase 4 (Gpx4). Single-cell transcriptomic analyses further identify the NFE2-related factor 2 (NRF2) antioxidant protective pathway as a female resilience mechanism against ferroptosis. Genetic inhibition and pharmacological activation studies show that NRF2 controls PT cell fate and plasticity by regulating ferroptosis. Importantly, pharmacological NRF2 activation protects male PT cells from ferroptosis and improves cellular plasticity as in females. Our data highlight NRF2 as a potential therapeutic target to prevent failed renal repair after acute kidney injury in both sexes by modulating cellular plasticity.

Identifiants

DOI: 10.1016/j.celrep.2022.111610 PMID: 36351395 PMC: PMC9795409
pubmed: 36351395
pii: S2211-1247(22)01479-6
doi: 10.1016/j.celrep.2022.111610
pmc: PMC9795409
mid: NIHMS1848906
pii:
doi:

Substances chimiques

NF-E2-Related Factor 2 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

111610

Subventions

Organisme : NIDDK NIH HHS
ID : P30 DK114857
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK121014
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK123097
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027528
Pays : United States

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

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Auteurs

Shintaro Ide (S)

Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.

Kana Ide (K)

Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.

Koki Abe (K)

Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.

Yoshihiko Kobayashi (Y)

Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA.

Hiroki Kitai (H)

Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.

Jennifer McKey (J)

Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA.

Sarah A Strausser (SA)

Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.

Lori L O'Brien (LL)

Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Aleksandra Tata (A)

Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA.

Purushothama Rao Tata (PR)

Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA; Duke Regeneration Center, Duke University School of Medicine, Durham, NC 27710, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA.

Tomokazu Souma (T)

Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Duke Regeneration Center, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: tomokazu.souma@duke.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Sex differences in resilience to ferroptosis...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Sex differences in resilience to ferroptosis...
questionsmedicales.fr › Eucaryotes › Animaux › Sex differences in resilience to ferroptosis...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Ferroptose › Sex differences in resilience to ferroptosis...
questionsmedicales.fr › Phénomènes physiologiques des appareils urinaire et reproducteur › Phénomènes physiologiques de la reproduction › Caractères sexuels › Sex differences in resilience to ferroptosis...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique et à glissière à leucines › Facteur-2 apparenté à NF-E2 › Sex differences in resilience to ferroptosis...
questionsmedicales.fr › Appareil urogénital › Voies urinaires › Rein › Sex differences in resilience to ferroptosis...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Maladies du rein › Insuffisance rénale › Atteinte rénale aigüe › Sex differences in resilience to ferroptosis...