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Abstract: TH-PO149

Differential Regulation of FGF23 Production and Cleavage by Iron and EPO in Anemic Mice

Session Information

  • CKD-MBD: Targets and Outcomes
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Hunt-Tobey, Bridget, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martinez-Calle, Marta, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Courbon, Guillaume, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Spindler, Jadeah Jeannine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Von Drasek, John Charles, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wang, Xueyan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Anemia affects over 2 billion people worldwide. In patients and animals, anemia leads to high circulating fibroblast growth factor (FGF)23 cleavage peptides due to simultaneous increased production and cleavage of intact (i)FGF23. Both iron deficiency and erythropoietin (EPO), which is secreted in response to anemia, independently increase FGF23 production and cleavage. However, their contribution to excess FGF23 in anemia is unknown.

Methods

To determine the contribution of iron deficiency and EPO to excess FGF23, we fed C57BL6/J mice from 3 to 6 weeks of age either control (Ctr), iron deficient (ID) or high iron (HI) diets to induce iron deficiency or iron overload anemia, respectively. In all mice, we measured hematological and iron metabolism parameters and circulating EPO and FGF23 levels.

Results

Both ID and HI mice developed anemia, as shown by similar and significant reductions of hemoglobin and red blood cell number. As a result, EPO levels increased in both ID and HI mice by 7 fold compared to Ctr mice. As expected, ID mice showed a reduction in iron, transferrin saturation (TSAT) and ferritin levels, as opposed to HI animals which showed higher iron, TSAT and ferritin compared to Ctr mice. As previously shown, ID triggered a 200% increase in total cFGF23 and a milder 20% increase in iFGF23 levels. In sharp contrast, anemic HI mice showed a 50% reduction in iFGF23 compared to Ctr mice, and only a 2 fold increase in total cFGF23 levels, suggesting that FGF23 cleavage increased despite normal FGF23 expression. In all mice, circulating total cFGF23 positively correlated with serum EPO levels. iFGF23 negatively correlated with serum iron, TSAT and ferritin only, but did not correlate with EPO levels.

Conclusion

In aggregate, these results suggest that iron deficiency, but not EPO, increases FGF23 production and that in anemia, elevated circulating EPO levels stimulate FGF23 cleavage independently of iron status.

Funding

  • NIDDK Support