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Abstract: TH-PO039

Myeloid Ferritin Heavy Chain Protects Against Ferroptosis in Ischemic AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Black, Laurence Marie, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Mccullough, Kayla R., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Traylor, Amie, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Boitet, Evan, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Lever, Jeremie M., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Esman, Stephanie, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Spangler, Daryll R., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Zarjou, Abolfazl, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Gross, Alecia K., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Bolisetty, Subhashini, University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Ferritin is classically involved in iron storage and metabolism and is made up of 24 subunits of two distinct types: light chain (FtL) and heavy chain (FtH). The latter confers ferroxidase activity, allowing for storage of iron in a safe, bioavailable form in the ferritin shell. Iron metabolism is in part regulated by myeloid cells. Furthermore, acute kidney injury (AKI) causes perturbations in iron metabolism, both highlighting the importance of studying the importance of FtH in preventing oxidative damage during AKI.

Methods

Previously characterized mice deficient in myeloid-FtH (FtHLysM-/-) and their floxed controls (FtHfl/fl) were subjected to bilateral renal ischemia-reperfusion injury (IR; 20 minutes). We measured renal function, inflammatory response, cell death, and cell proliferation on days 1 and 2 post-IR.

Results

Though FtHLysM-/- and FtHfl/fl mice both experienced a similar rise in serum creatinine levels (FtHfl/fl1.6 ± 0.11 mg/dL; FtHLysM-/- 1.3 ± 0.12 mg/dL) and structural damage on day 1 following IR, renal function and damage in myeloid-FtH deficient mice continued to worsen (2.4 ± 0.38 mg/dL), which subsequently results in mortality. Interestingly, FtHLysM-/- mice also had lesser polymorphonuclear (PMN), natural killer, B, and T cell density post-IR compared to floxed controls, as well as significantly exacerbated cell death (p<0.0001) as early as 1-day post-IR. Myeloid-FtH deficiency also was associated with reduced cell proliferation after IR. Due do perturbations observed in iron metabolism in FtHLysM-/- mice, we hypothesized that treatment with ferrostatin-1 (Fer-1), a potent ferroptosis inhibitor, would ameliorate injury in the absence of myeloid FtH. Here, we report significant protection from AKI by serum creatinine in FtHLysM-/- mice treated with Fer-1 (0.97± 0.29 mg/dL), compared to vehicle controls (2.05 ± 0.36 mg/dL).

Conclusion

Our findings demonstrate for the first time a crucial role for myeloid FtH in protecting against ferroptosis in renal IR. This study highlights the significance of controlling iron metabolism during injury for AKI resolution and prevention of disease.

Funding

  • NIDDK Support