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Abstract: TH-PO106

Mouse Model of Local Iron Homeostasis Disruption in AKI

Session Information

  • AKI: Mechanisms - I
    November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Soofi, Abdul A., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Li, Vivie, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Beamish, Jeffrey A., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Dressler, Greg R., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Iron plays an essential role in many critical biological processes including oxygen transport, cell proliferation, and regeneration. However, when iron is present in excess, it is toxic to the kidneys. Acute kidney injury (AKI) and iron-related disorders are associated with significant morbidity and mortality. Dysregulation of iron homeostasis plays an important pathogenic role in kidney disease, but limited data are available on successful iron targeting therapies in AKI. Ferroportin (FPN) is expressed in the kidney and is known as the iron exporter and central regulator of iron metabolism, but its function in the pathogenesis of AKI still unclear. Through this work, we will determine whether the disruption of local iron homeostasis by selective depletion of FPN in renal proximal tubules cells (PTCs) alters the response to AKI.


We are testing this hypothesis by generating conditional knockout mice to target iron trafficking proteins and determine their roles in AKI and the molecular and genetic mechanisms regenerating of PTCs. We selectively expressed Cre in PTCs with a Pepck promoter (PepcK-Cre) and confirmed deletion with a red-green reporter (mT/mG) to produce FPNf/f; Pepck-cre; mT/mG (FPN-KO) mice.


FPN-KO mice were generated and deletion of FPN was confirmed. Mutant mice showed no gross morphology or renal phenotype. FPN-OK and controls mice were subjected to either folic acid or renal ischemia-reperfusion models. Blood and tissue samples were collected at 0, 2, 7, and 28 days after injury. Kidney function and iron deposition were measured. Histology, immunohistochemistry, RNA isolation, and immunoblot analysis and qualification were performed. Data indicate that FPN-KO mice subjected to AKI models developed pronounced iron deposition in PTCs. Damaged tubules lead to worsening interstitial fibrosis, ferroptosis, and failure to recover and regenerate injured tubules compared to controls.


Despite the essential role in life, excessive iron is toxic due to its ability to generate reactive oxygen species. Disrupting iron trafficking in PTCs by manipulating the expression of FPN increases AKI severity and impairs recovery. Understanding the molecular mechanisms underlying the regulation of local iron homeostasis and ferroptosis may provide therapeutic strategies for progressive kidney disease and ferroptosis-associated disorders.


  • Other NIH Support