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Kidney Week

Abstract: TH-PO107

Myeloid Heavy Chain Ferritin Mitigates Ischemic AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Black, Laurence Marie, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Traylor, Amie, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Mccullough, Kayla R., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Lever, Jeremie M., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Jiang, Yanlin, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Osis, Gunars, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Zarjou, Abolfazl, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Bolisetty, Subhashini, University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Acute kidney injury (AKI) stimulates crosstalk between damaged renal tubular epithelium and infiltrating inflammatory cells by chemokine and cytokine release. Perpetual inflammation drives worsened kidney function, structural damage and fibrosis, highlighting the importance of understanding immune cell trafficking in AKI. Heavy chain ferritin (FtH), a protein with ferroxidase activity responsible for iron metabolism, is implicated in macrophage polarization. Here, we investigate the role of myeloid FtH in immune cell trafficking and resolution of AKI.

Methods

We subjected mice deficient in myeloid FtH (FtHLysM-/-) and floxed controls (FtHfl/fl) to bilateral renal ischemia-reperfusion injury (IR, 20 minutes). We measured renal function, structural damage, chemokine and cytokine expression, and inflammatory cell infiltration.

Results

FtHfl/fl and FtHLysM-/- mice experience similar functional (serum creatinine; SCr levels (FtHfl/fl 1.6 ± 0.11 mg/dL; FtHLysM-/- 1.3 ± 0.12 mg/dL) and structural damage at day 1. At day 2, only FtHLysM-/- mice continue to worsen (2.4 ± 0.38 mg/dL), which subsequently results in significant mortality. FtHLysM-/- mice also exhibit elevated levels of growth differentiation factor-15, a marker of renal injury, at day 2 while FtHfl/fl levels are significantly decreased. Interestingly, day 2 after IR, while chemokine and cytokine expression in FtHfl/fl mice is reduced, levels of intrarenal inflammatory markers, such as CXCL2 and IL-6, and serum IL-5 remain elevated in FtHLysM-/- mice. Following IR, the absolute number of intrarenal F4/80int/low CD11b+ Ly6Clow/neg CD11c+ mononuclear phagocytes in FtHfl/fl mice increases, while this cell population does not change from sham levels in FtHLysM-/- mice. After IR, FtHfl/fl mice have a robust induction of neutrophil elastase, an enzyme important for digestion of cellular debris, while it is significantly blunted in FtHLysM-/- mice.

Conclusion

Our findings demonstrate that, while deletion of myeloid FtH does not influence the ischemic insult to the kidney, it regulates the resolution of AKI potentially via activation of pro-resolving macrophages. This study underscores the significance of harnessing macrophages in immunotherapy for AKI resolution and prevention of chronic kidney disease.

Funding

  • NIDDK Support