# Changes in phosphate metabolism cause pathologic cardiac remodeling in chronic kidney disease (CKD)

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $584,924

## Abstract

ABSTRACT
Fibroblast growth factor (FGF) 23 is a bone-derived hormone that targets the kidney via FGF receptors (FGFR)
and klotho, a transmembrane protein (‘mKL’) that acts as an FGF23 co-receptor, thereby increasing renal
phosphate excretion and lowering serum phosphate levels. In patients with chronic kidney disease (CKD),
FGF23-responsiveness and phosphate reabsorption are impaired, leading to increased serum phosphate
concentrations and FGF23 production in bone. Clinical studies have shown that elevated serum FGF23 levels
are strongly associated with negative outcomes in CKD, such as cardiac hypertrophy and cardiovascular
mortality. Our translational work indicates that circulating FGF23 can directly contribute to tissue injury that is
associated with CKD. By activating FGF receptor (FGFR) 4 and subsequent phospholipase C
(PLC)/calcineurin/nuclear factor of activated T cells (NFAT) signaling in cardiac myocytes, FGF23 induces
cardiac hypertrophy and fibrosis in rodents. This pathologic effect occurs independently of klotho that is not
expressed in the heart. Klotho also exists in a truncated soluble form (‘sKL’) that is generated by proteolysis of
mKL and released from the kidney. Experimental studies indicate that sKL has tissue-protective effects, including
anti-hypertrophic and anti-fibrotic actions in the heart, similar to active vitamin D (‘1,25D‘), which also acts as a
cardio-protective hormone. In patients with CKD, serum levels of sKL and 1,25D are significantly reduced, and
it is thought that a loss of sKL’s and 1,25D’s protective effects contributes to CKD-associated tissue injury. Since
our published and preliminary work indicates that sKL and 1,25D can inhibit FGF23-induced signaling and
hypertrophy in cultured cardiac myocytes, we hypothesize that sKL and 1,25D attenuate pathologic actions of
FGF23 in the heart. In Aim 1, we will study in mice on an adenine-rich diet (AD), a model for CKD with high
FGF23 that develops cardiac hypertrophy, whether systemic sKL elevations by AAV delivery attenuate cardiac
hypertrophy, and vise-versa, whether the absence of sKL in a mouse model with kidney-specific klotho deletion
accelartes cardiac injury. In isolated cardiac myocytes, we will study the mechanism underlying sKL’s anti-
hypertrophic effects and determine if by interacting with FGF23, sKL can block FGF23 binding to FGFR4 and/or
FGFR4 activation. In Aim 2, we will determine if administration of 1,25D has cardio-protective effects in mice on
AD, as well as in genetically modified mice with constitutive FGFR4 activation and cardiac hypertrophy. We will
also study if in mice with cardiac-specific deletion of the vitamin receptor (VDR) which spontaneously develop
cardiac hypertrophy, the elevation of serum FGF23 levels by AD or by osmotic minipump infusions of
recombinant FGF23 aggravates cardiac injury. We postulate that via the studied mechanism, elevated serum
FGF23, and reduced serum levels of sKL and 1,25D, three clinical hallmarks ...

## Key facts

- **NIH application ID:** 9852473
- **Project number:** 5R01HL145528-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Christian Faul
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $584,924
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852473

## Citation

> US National Institutes of Health, RePORTER application 9852473, Changes in phosphate metabolism cause pathologic cardiac remodeling in chronic kidney disease (CKD) (5R01HL145528-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852473. Licensed CC0.

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