Multiple oestradiol functions inhibit ferroptosis and acute kidney injury

Acute tubular necrosis mediates acute kidney injury (AKI) and nephron loss, the hallmark of end-stage renal disease. For decades, it has been known that female kidneys are less sensitive to AKI. Acute tubular necrosis involves dynamic cell death propagation by ferroptosis along the tubular compartment. Here we demonstrate abrogated ferroptotic cell death propagation in female kidney tubules. 17β-oestradiol establishes an anti-ferroptotic state through non-genomic and genomic mechanisms. These include the potent direct inhibition of ferroptosis by hydroxyoestradiol derivatives, which function as radical trapping antioxidants, are present at high concentrations in kidney tubules and, when exogenously applied, protect male mice from AKI. In cells, the oxidized hydroxyoestradiols are recycled by FSP1, but FSP1-deficient female mice were not sensitive to AKI. At the genomic level, female ESR1-deficient kidney tubules partially lose their anti-ferroptotic capacity, similar to ovariectomized mice. While ESR1 promotes the anti-ferroptotic hydropersulfide system, male tubules express pro-ferroptotic proteins of the ether lipid pathway which are suppressed by ESR1 in female tissues until menopause. In summary, we identified non-genomic and genomic mechanisms that collectively explain ferroptosis resistance in female tubules and may function as therapeutic targets for male and postmenopausal female individuals.

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Publication Details

Journal
Universität Zürich, ZORA
Published
2025-09-01
DOI
https://doi.org/10.5167/uzh-291834
Primary Topic
Ferroptosis and cancer prognosis
Type
article
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article

Multiple oestradiol functions inhibit ferroptosis and acute kidney injury

Andrej Shevchenko, Danny Schilling, Alexia Belavgeni, Majid Katebi et al.
Universität Zürich, ZORA
Ferroptosis and cancer prognosis
article

Multiple oestradiol functions inhibit ferroptosis and acute kidney injury

Andrej Shevchenko, Danny Schilling, Alexia Belavgeni, Majid Katebi, Marlena Nastassja Schlecht, Christine Gaillet, J. Becker, Mirko Peitzsch, Shubhangi Gavali, Sider Penkov, Nina Himmerkus, Melodie Mallais, Wulf Tonnus, Anne Brucker, Karolin Flade, Lisa Schlicker, Francesca Maremonti, Florian Gembardt, Sonia Nasi, Almut Schulze, Juliane Putz, Sofia Traikov, Mirela Tmava, Nadja Leinung, Natalie Bethe, Louisa M. S. Gerhardt, Anne Haag, Anushka Ray, Uladzimir Barayeu, et al., Claudia Meyer, Stefan R Bornstein
article en

Abstract

Acute tubular necrosis mediates acute kidney injury (AKI) and nephron loss, the hallmark of end-stage renal disease. For decades, it has been known that female kidneys are less sensitive to AKI. Acute tubular necrosis involves dynamic cell death propagation by ferroptosis along the tubular compartment. Here we demonstrate abrogated ferroptotic cell death propagation in female kidney tubules. 17β-oestradiol establishes an anti-ferroptotic state through non-genomic and genomic mechanisms. These include the potent direct inhibition of ferroptosis by hydroxyoestradiol derivatives, which function as radical trapping antioxidants, are present at high concentrations in kidney tubules and, when exogenously applied, protect male mice from AKI. In cells, the oxidized hydroxyoestradiols are recycled by FSP1, but FSP1-deficient female mice were not sensitive to AKI. At the genomic level, female ESR1-deficient kidney tubules partially lose their anti-ferroptotic capacity, similar to ovariectomized mice. While ESR1 promotes the anti-ferroptotic hydropersulfide system, male tubules express pro-ferroptotic proteins of the ether lipid pathway which are suppressed by ESR1 in female tissues until menopause. In summary, we identified non-genomic and genomic mechanisms that collectively explain ferroptosis resistance in female tubules and may function as therapeutic targets for male and postmenopausal female individuals.

Universität Zürich, ZORA
Good health and well-being
Openalex Percentile: Top 24%
Ferroptosis and cancer prognosis
DOIOpen Access PDFOpenAlex
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