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Abstract: PO0330

β-Estradiol Protects from Ferroptosis and Explains the Higher Sensitivity of Murine Male vs. Female Kidney Tubules to Acute Tubular Necrosis

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Belavgeni, Alexia, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany
  • von Mässenhausen, Anne, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany
  • Tonnus, Wulf, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany
  • Maremonti, Francesca, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany
  • Meyer, Cloudy, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany
  • Hugo, Christian, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany
  • Weinberg, Joel M., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Linkermann, Andreas, Universitatsklinikum Carl Gustav Carus, Dresden, Sachsen, Germany
Background

In several preclinical models of acute kidney injury (AKI), male mice are known to exhibit a higher sensitivity compared to females, but mechanistic insights to explain this observation have been lacking over decades. Acute tubular necrosis (ATN) is a common feature of AKI the sensitivity to which might explain this long-standing obstacle.

Methods

Isolated murine kidney tubules were assessed with cell death assays (e.g. LDH release assay).

Results

Here, we demonstrated in isolated murine kidney tubules that spontaneous ATN is a regulated event. While tubules isolated from combined necroptosis- and pyroptosis-deficient mice (MLKL/GSDMDDKO) did not show different LDH release levels compared to control, inhibition of ferroptosis by the ferroptosis inhibitor ferrostatin 1 (Fer-1) significantly protected wild type tubules. Importantly, we detected less spontaneous necrosis in female versus male tubules. While female tubules exhibited resistance to LDH release, male tubules were sensitive but could be protected by co-incubation with Fer-1. Tubular sex specific differences could not be explained by potential pro-ferroptotic effects of testosterone but rather by anti-ferroptotic effects of β-estradiol.

Conclusion

In summary, while these data confirm the involvement of ferroptosis in spontaneous tubular necrosis, we identify β-estradiol as a general inhibitor of ferroptosis. This anti-ferroptotic effect explains the difference in sensitivity toward ATN of renal tubules of male and female mice.

Funding

  • Government Support – Non-U.S.