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Abstract: TH-PO705

Iron Therapy Mitigates Kidney Fibrosis by Regulating Intracellular Iron Status of Kidney Macrophages

Session Information

  • Anemia and Iron Metabolism
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms


  • Patino, Edwin, Weill Cornell Medicine, New York, New York, United States
  • Bhatia, Divya, Weill Cornell Medicine, New York, New York, United States
  • Jaouni, Shahd, Weill Cornell Medicine, New York, New York, United States
  • Uni, Rie, Weill Cornell Medicine, New York, New York, United States
  • Castillo, Carlo G., Weill Cornell Medicine, New York, New York, United States
  • Vinchi, Francesca, New York Blood Center, New York, New York, United States
  • Choi, Mary E., Weill Cornell Medicine, New York, New York, United States
  • Akchurin, Oleh M., Weill Cornell Medicine, New York, New York, United States

Systemic iron metabolism is disrupted in CKD. However, little is known about local kidney iron homeostasis and its role in kidney fibrosis. Kidney-specific effects of iron therapy in CKD also remain elusive. Here, we assess the role of macrophage iron status in kidney fibrosis and report preclinical data suggesting that it can be used as a therapeutic target.


We used two mouse models of kidney fibrosis: adenine diet and unilateral urethral obstruction (UUO), applied to wild type mice and to ferritin heavy chain (Fth1) myloid-specific (LysM-cre) knockout mice. A subset of mice received weekly intraperitoneal injections of iron dextran (0.5 g/kg body weight) or adoptive transfer of iron-loaded macrophages. Mice were euthanized after 8 weeks of adenine diet or 7 days after UUO. Kidney macrophages were analyzed by flow cytometry using single cell suspensions of homogenized and digested kidney tissues. Effects of iron on macrophage phenotype were also assessed in vitro with and without concurrent TGF-β stimulation.


In both models of kidney fibrosis, kidney macrophages exhibited depletion of labile iron pool (LIP) and induction of transferrin receptor 1, indicating intracellular iron deficiency. Low LIP in kidney macrophages was associated with their defective antioxidant response and pro-inflammatory polarization. Repletion of LIP in kidney macrophages through knockout of Fth1 reduced oxidative stress and mitigated fibrosis. Iron significantly decreased TGF-β expression and suppressed TGF-β-driven fibrotic response of macrophages. Similar to Fth1 knockout, iron dextran therapy, through replenishing macrophage LIP, reduced oxidative stress, decreased production of pro-inflammatory cytokines, and alleviated kidney fibrosis. Iron dextran therapy and FtH suppression had additive protective effect against fibrosis. Adoptive transfer of iron-loaded macrophages also alleviated kidney fibrosis, confirming the protective effect of iron-replete macrophages in CKD.


Depletion of LIP in kidney macrophages paradoxically drives their pro-oxidative, pro-inflammatory, and pro-fibrotic qualities in CKD. Repletion of intracellular LIP in macrophages attenuates kidney fibrosis. Thus, intracellular iron status of kidney macrophages appears to be a promising therapeutic target in CKD.


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