# FGF23 contributes to anemia in Chronic Kidney Disease by elevating hepcidin  production

> **NIH NIH F31** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $31,338

## Abstract

PROJECT SUMMARY
Chronic Kidney Disease (CKD) is a health epidemic that increases the risk of death due to systemic inflammation
and anemia which affects up to 60% of patients by the time they reach dialysis. Early metabolic complications of
CKD, such as elevated serum concentrations of bone-derived fibroblast growth factor (FGF) 23, are strongly
associated with increased levels of inflammatory cytokines, such as interleukin-6 (IL-6) and C-reactive protein
(CRP), and of iron regulators, including hepcidin, and with mortality. In a recent experimental study, we
demonstrated that FGF23 contributes to inflammation by directly targeting hepatocytes through FGF receptor
isoform 4 (FGFR4) and inducing PLCγ/calcineurin/NFAT signaling and the production of IL-6 and CRP. We found
that animal models with FGF23 elevations have increased hepatic and circulating levels of IL-6 and CRP, which
did not occur if FGFR4 was blocked or deleted. IL-6 is a potent inducer of hepcidin production in the liver by
activating IL-6 receptor (IL-6R) and signal transducer and activator of transcription 3 (STAT3) signaling in
hepatocytes. Hepcidin lowers serum iron levels by reducing iron absorption in different cell types, including
hepatocytes. Prolonged elevations of serum hepcidin levels, as observed in CKD, result in iron deficiency, and
the reduction of hepcidin production can serve as a therapeutic approach to tackle anemia. The purpose of this
proposal is to study functional interactions between FGF23, IL-6 and hepcidin. We postulate that by increasing
IL-6 production, FGF23 can elevated hepatic and systemic levels of hepcidin and contribute to anima. This
hypothesis is supported by our preliminary data showing that FGF23 significantly increases hepcidin expression
in primary mouse hepatocytes. This effect occurs only after 48 hours of FGF23 treatment and involves the
activation of STAT3. In Aim 1, we will determine if phosphorylation and transcriptional activity of STAT3 as well
as expression and release of hepcidin in FGF23-treated mouse hepatocytes is reduced by inhibitors of the
PLCγ/calcineurin/NFAT or the IL-6R/JAK/STAT3 signaling pathways. We will repeat the experiment in
hepatocytes isolated from FGFR4 knockout (FGFR4-/-) mice or following viral knockdown of IL-6 or IL-6R. In Aim
2, we will determine if deletion or blockade of FGFR4 in animal models with elevated FGF23 reduces hepcidin
production and protects from anemia. We have reported that administration of FGF23 in mice increases hepatic
and circulating levels of IL-6 within five days. Our preliminary studies indicate that Alport mice, a genetic model
of CKD with high FGF23 levels, show elevated IL-6 and hepcidin expression in the liver and develop anemia.
We will subject FGFR4-/- mice to chronic FGF23 infusions using osmotic minipumps, and we will administer a
FGFR4-specific small molecule inhibitor to Alport mice, followed by the analysis of IL-6 and hepcidin expression
in the liver and of serological iron...

## Key facts

- **NIH application ID:** 9948489
- **Project number:** 5F31DK117550-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Brian Czaya
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,338
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-04-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948489

## Citation

> US National Institutes of Health, RePORTER application 9948489, FGF23 contributes to anemia in Chronic Kidney Disease by elevating hepcidin  production (5F31DK117550-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948489. Licensed CC0.

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