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Kidney Week

Abstract: PO0406

The Role of Disrupted Iron Metabolism in AKI: Targeting Iron Trafficking via the Hepcidin-Ferroportin Axis in Renal Proximal Tubules

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Soofi, Abdul A., University of Michigan, Ann Arbor, Michigan, United States
  • Beamish, Jeffrey A., University of Michigan, Ann Arbor, Michigan, United States
  • Dressler, Greg R., University of Michigan, Ann Arbor, Michigan, United States
  • Hamad, Mawieh, University of Sharjah, Sharjah, Sharjah, United Arab Emirates
Background

Acute Kidney injury (AKI) and iron-related disorders remain major clinical challenges associated with significant morbidity and mortality. Ferroportin (FPN) is an iron exporter, identified as a modulator of iron balance. Hepcidin binds to FPN, causing its internalization and degradation. Though FPN and Hepcidin are expressed in proximal tubule cells (PTCs) of the mouse kidney, their role in the pathogenesis of AKI is unclear. Through this work, we hope to determine if modulation of iron homeostasis by selective depletion of hepcidin or FPN in PTCs alters the response to AKI.

Methods

We generated PTCs-specific Hepcidin1 and Ferroportin (FPN) knockout (KO) by selectively expressing Cre in PTCs and confirmation with a red-green reporter (mT/mG; Pepck-cre) allele. We subjected these mice to either the Folic Acid induced injury model or the ischemia-reperfusion injury models of AKI. Serum samples were collected at 2, 7, 14, 21, and 28 days after injury and BUN, creatinine, iron, and ferritin level were measured. Kidney tissues were collected at each time point for histology, iron deposition, immunohistochemistry, RNA isolation, and immunoblot analysis.

Results

Conditional KO mice were generated and deletion of Hepcidin1 and FPN specifically in PTCs was confirmed at the DNA and protein levels. Mutant young adult mice showed no gross morphology phenotype. However, both mutant strains developed pronounced iron deposition in PTCs measured with DAB-enhanced Perls stain for iron which further increased following injury. After AKI, mutant mice failed to recover and regenerate damaged tubules leading worsening interstitial fibrosis, necrosis, and ferroptosis compared with wild type mice of the same genetic background. Markers of fibrosis, ferroptosis, and levels of ferritin will be quantified in serum and kidney tissue.

Conclusion

Our preliminary data indicate that disrupting iron trafficking in PTCs by manipulating the expression of FPN and hepcidin increases AKI severity and impairs recovery. These findings may offer new insights into the role of iron metabolism in AKI and illuminate new therapeutic strategies for progressive kidney disease and other syndromes of iron overload.