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Abstract: PO0360

Targeting Myeloid Ferritin Heavy Chain (FtH) in Rhabdomyolysis-Induced AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Mccullough, Kayla R., Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Taheri, Mauhaun, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Hudson, Matthew C., Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Traylor, Amie, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Bolisetty, Subhashini, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Acute kidney injury (AKI) is defined as an abrupt decrease in kidney function and significantly impacts mortality. During rhabdomyolysis, muscle injury leads to release of myoglobin, causing an increased heme/iron delivery to the kidney, leading to AKI. Iron exacerbates oxidative stress and causes cell death. Kidneys respond to increased iron by inducing ferritin heavy chain (FtH) expression. FtH is a ferroxidase that converts ferrous iron into ferric form. Distinct myeloid populations promote injury and depletion of macrophages protect against rhabdomyolysis. Myeloid cells express high levels of FtH and mediate iron recycling. Therefore, we tested the hypothesis that myeloid FtH confers protection against rhabdomyolysis-induced AKI.

Methods

To induce rhabdomyolysis, female mice (10-12 weeks) deficient in myeloid FtH (FtHLysm-/-) and floxed controls (FtHfl/fl) were deprived of water for 16 h and administered 50% glycerol via intramuscular injection into hindlimbs (7.5 or 11 ml/kg body weight). Mice were harvested at 1-, 3-, or 7-days post-glycerol. Kidney function and injury were evaluated by serum creatinine, and kidney injury marker 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) expression, respectively. Kidneys were analyzed for markers of cell injury/death (KIM-1, calcium-binding protein A8 (S100A8)), cleaved caspase 3 (CC3) and TUNEL positivity and fibrosis.

Results

Rhabdomyolysis led to a significant loss in kidney function and an increase in kidney injury (NGAL and KIM-1) in all groups of mice. However, at 7 days, while these markers returned to baseline in FtHLysm-/- mice, there was a persistent tripling of creatinine and elevated KIM-1 levels only in FtHfl/fl mice. This was associated with increased activation of JNK, and markers of cell death. Additionally, FtHfl/fl kidneys expressed higher levels of aSMA and collagen when compared to FtHLysm-/- kidneys. This was associated with increased expression of TGFb and Gal-3, which mediate myofibroblast activation and promote fibrosis.

Conclusion

Our findings demonstrate that while myeloid FtH deletion does not impact acute injury following rhabdomyolysis, it mitigates injury progression and promotes recovery. Current studies are aimed at using single cell RNA sequencing approaches to identify key pathways that are activated during the resolution phase following rhabdomyolysis.

Funding

  • NIDDK Support