Evidence of Renal Iron and FGF23 Signaling Interdependence on Vitamin D Homeostasis in Sickle Cell Disease

Emily Winnicki

Document Type

Article

Publication Date

2024

Keywords

JMG

JAX Location

In: Student Reports, Summer 2024, The Jackson Laboratory

Abstract

Hemolysis in sickle cell disease (SCD) leads to high circulating heme and kidney iron deposits. Kidney proximal tubular cells regulate vitamin D (VitD) synthesis enzymes. VitD deficiency is a common complication of SCD linked to poor disease outcomes. The bone-derived hormone, fibroblast growth factor 23 (FGF23), signals in the kidney to activate the VitD catabolite enzyme CYP24A1 and represses the anabolite enzyme CYP27B1, contributing to VitD regulation. Using SCD transgenic mouse model and in vitro methods, we tested the impact of proximal tubular iron loading and FGF23 signaling on VitD metabolism. In the bone compartment, FGF23 levels increased in SCD mice compared to wild-type mice, which is associated with renal iron loading as assessed by the iron deposition marker, FTH1. In SCD mice, the expression of CYP24A1 decreased by 80%, while CYP27B1 remained steady. To test whether VitD enzymes regulation is driven by iron, we fed C57BL/6J mice with iron overload diet to mimic renal iron loading. We found that iron represses CYP24A1 and increases CYP27B1 in the kidney. Using engineered Human Embryonic Kidney 293 cells, we found that iron overloading promotes FGF23 signaling as assessed by the biomarker, EGR1. Taken together, our results indicate that renal iron and FGF23 signaling effects on VitD regulation are interdependent and both may be required to adequately regulate VitD. Mechanistically, iron-mediated CYP24A1 down-regulation is a compensatory mechanism for FGF23-mediated CYP24A1 up-regulation. Understanding the implications of iron and FGF23 pathways on VitD metabolism could help in designing future therapies for managing SCD severity.

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