Abstract: TH-PO0239
Hepatic Hepcidin Deficiency Drives Iron-Mediated Renal Ferroptosis and Chronic Kidney Injury
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Soofi, Abdul A., University of Michigan, Ann Arbor, Michigan, United States
- Thompson, Austin Dennis, University of Michigan, Ann Arbor, Michigan, United States
- Qamhieh, Ibrahim, University of Michigan, Ann Arbor, Michigan, United States
- Pennathur, Subramaniam, University of Michigan, Ann Arbor, Michigan, United States
Background
Hepcidin controls systemic iron homeostasis via ferroportin suppression. Ferroptosis, iron dependent cell death driven by lipid peroxidation, GPX4 suppression, and ACSL4 activation, drives kidney injury in CKD. While pharmacologically implicated in tubular injury, no genetic model has established hepcidin deficiency as an upstream initiator. We report hepatic hepcidin deletion mice, revealing a renal ferroptotic phenotype from systemic iron overload independent of renal hepcidin.
Methods
Hepcidin conditional knockout mice (Hamp1fl/fl; Albumin Cre; mT/mG; Hepcidin LKO) were generated with hepatocyte Cre recombination confirmed by GFP. Iron was assessed in tissue, serum, and urine. Ferroptosis markers included GPX4, ACSL4, 4HNE, MDA, and TfR1 dimer formation. Glomerular endothelial injury was assessed by PLVAP and CD31 with SEM confirmation. Tubular injury was assessed by CD9. Pan14-3-3 was evaluated in tissue and urine as a dual compartment marker. Fibrosis was quantified by trichrome, collagen, and α-SMA. Renal hepcidin was assessed by immunofluorescence.
Results
Hepcidin LKO mice developed progressive systemic iron overload confirmed by serum and urinary indices. Liver showed iron deposition with collagen, α-SMA, and trichrome positive fibrosis. Kidneys demonstrated iron accumulation with ferroptotic signatures including suppressed GPX4, elevated ACSL4, 4HNE, MDA, and upregulated TfR1 dimers. PLVAP induction and CD31 alterations confirmed glomerular endothelial injury; CD9 dysregulation confirmed tubular injury. Pan14-3-3 showed glomerular vesicle formation and tubular upregulation correlating with urinary secretion, establishing it as a novel dual compartment biomarker. Renal hepcidin was unchanged, confirming injury arises from systemic iron excess not local dysregulation.
Conclusion
Hepatic hepcidin deficiency drives compartment specific renal ferroptosis independent of renal hepcidin. PLVAP, CD9, and Pan14-3-3 define a compartment resolved injury signature alongside TfR1 dimers as a ferroptosis specific marker. These findings establish the hepcidin/iron axis as an upstream driver of renal ferroptotic injury and the first genetic platform for iron amplified ferroptosis.
Funding
- NIDDK Support