Tonnus Wulf, Maremonti Francesca, Gavali Shubhangi, Schlecht Marlena Nastassja, Gembardt Florian, Belavgeni Alexia, Leinung Nadja, Flade Karolin, Bethe Natalie, Traikov Sofia, Haag Anne, Schilling Danny, Penkov Sider, Mallais Melodie, Gaillet Christine, Meyer Claudia, Katebi Melika, Ray Anushka, Gerhardt Louisa M S, Brucker Anne, Becker Jorunn Naila, Tmava Mirela, Schlicker Lisa, Schulze Almut, Himmerkus Nina, Shevchenko Andrej, Peitzsch Mirko, Barayeu Uladzimir, Nasi Sonia, Putz Juliane, Korach Kenneth S, Neugarten Joel, Golestaneh Ladan, Hugo Christian, Becker Jan Ulrich, Weinberg Joel M, Lorenz Svenja, Proneth Bettina, Conrad Marcus, Wolf Eckhard, Plietker Bernd, Rodriguez Raphaël, Pratt Derek A, Dick Tobias P, Fedorova Maria, Bornstein Stefan R, Linkermann Andreas
Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
Department of Medicine V, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.
Nature. 2025 Aug 13. doi: 10.1038/s41586-025-09389-x.
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.
急性肾小管坏死介导急性肾损伤（AKI）和肾单位丢失，这是终末期肾病的标志。几十年来，人们已经知道雌性肾脏对急性肾损伤的敏感性较低。急性肾小管坏死涉及铁死亡沿肾小管腔的动态细胞死亡传播。在这里，我们证明了雌性肾小管中铁死亡性细胞死亡传播的消除。17β-雌二醇通过非基因组和基因组机制建立了一种抗铁死亡状态。这些机制包括羟基雌二醇衍生物对铁死亡的有效直接抑制，羟基雌二醇衍生物作为自由基捕获抗氧化剂，在肾小管中高浓度存在，并且在体外应用时可保护雄性小鼠免受急性肾损伤。在细胞中，氧化的羟基雌二醇由FSP1循环利用，但FSP1缺陷的雌性小鼠对急性肾损伤不敏感。在基因组水平上，雌性ESR1缺陷的肾小管部分丧失了其抗铁死亡能力，这与去卵巢小鼠相似。虽然ESR1促进抗铁死亡的氢过硫化物系统，但雄性肾小管表达醚脂途径的促铁死亡蛋白，这些蛋白在雌性组织中直到绝经前都受到ESR1的抑制。总之，我们确定了非基因组和基因组机制，这些机制共同解释了雌性肾小管中的铁死亡抗性，并且可能作为雄性和绝经后女性个体的治疗靶点。
