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

Abstract

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.

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Citation

Published Version (Please cite this version)

10.1016/j.celrep.2022.111610

Publication Info

Ide, Shintaro, Kana Ide, Koki Abe, Yoshihiko Kobayashi, Hiroki Kitai, Jennifer McKey, Sarah A Strausser, Lori L O'Brien, et al. (2022). Sex differences in resilience to ferroptosis underlie sexual dimorphism in kidney injury and repair. Cell reports, 41(6). p. 111610. 10.1016/j.celrep.2022.111610 Retrieved from https://hdl.handle.net/10161/29041.

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Scholars@Duke

Tata

Aleksandra Tata

Assistant Research Professor of Cell Biology
Tata

Purushothama Rao Tata

Associate Professor of Cell Biology

Lung regeneration
Lung stem cells
Cell plasticity
Organoid models
Lung Fibrosis
Single Cell Biology

Souma

Tomokazu Souma

Assistant Professor in Medicine

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