Kidney Week

Abstract: TH-PO107

Myeloid Heavy Chain Ferritin Mitigates Ischemic AKI

Session Information

• AKI: Inflammation, New Technologies, Omics
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Black, Laurence Marie, University of Alabama at Birmingham, Birmingham, Alabama, United States

Laurence Marie Black,

• Traylor, Amie, University of Alabama at Birmingham, Birmingham, Alabama, United States

Amie Traylor,

• Mccullough, Kayla R., University of Alabama at Birmingham, Birmingham, Alabama, United States

Kayla R. Mccullough,

• Lever, Jeremie M., University of Alabama at Birmingham, Birmingham, Alabama, United States

Jeremie M. Lever,

• Jiang, Yanlin, University of Alabama at Birmingham, Birmingham, Alabama, United States

Yanlin Jiang,

• Osis, Gunars, University of Alabama at Birmingham, Birmingham, Alabama, United States

Gunars Osis,

• Zarjou, Abolfazl, University of Alabama at Birmingham, Birmingham, Alabama, United States

Abolfazl Zarjou,

• Bolisetty, Subhashini, University of Alabama at Birmingham, Birmingham, Alabama, United States

Subhashini Bolisetty,

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 (FtH^LysM-/-) and floxed controls (FtH^fl/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

FtH^fl/fl and FtH^LysM-/- mice experience similar functional (serum creatinine; SCr levels (FtH^fl/fl 1.6 ± 0.11 mg/dL; FtH^LysM-/- 1.3 ± 0.12 mg/dL) and structural damage at day 1. At day 2, only FtH^LysM-/- mice continue to worsen (2.4 ± 0.38 mg/dL), which subsequently results in significant mortality. FtH^LysM-/- mice also exhibit elevated levels of growth differentiation factor-15, a marker of renal injury, at day 2 while FtH^fl/fl levels are significantly decreased. Interestingly, day 2 after IR, while chemokine and cytokine expression in FtH^fl/fl mice is reduced, levels of intrarenal inflammatory markers, such as CXCL2 and IL-6, and serum IL-5 remain elevated in FtH^LysM-/- mice. Following IR, the absolute number of intrarenal F4/80^int/low CD11b⁺ Ly6C^low/neg CD11c⁺ mononuclear phagocytes in FtH^fl/fl mice increases, while this cell population does not change from sham levels in FtH^LysM-/- mice. After IR, FtH^fl/fl mice have a robust induction of neutrophil elastase, an enzyme important for digestion of cellular debris, while it is significantly blunted in FtH^LysM-/- 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