Chronic kidney disease (CKD) is a public health problem that increases the risk of cardiovascular disease and death. By promoting heart failure, cardiac hypertrophy is an important pathology in CKD and affects up to 90% of patients by the time they reach dialysis. Elevated serum levels of bone-derived fibroblast growth factor (FGF) 23 are a common, early metabolic complication of CKD that is strongly associated with cardiovascular events and mortality. In recent experimental studies, we demonstrated that in this context, FGF23 might act as a causal factor by directly targeting cardiac myocytes and inducing cardiac hypertrophy. We could show that FGF23 can specifically activate FGF receptor isoform 4 (FGFR4) and subsequent PLC?/calcineurin/NFAT signaling leading to hypertrophic growth of cardiac myocytes that occurs independently of elevations in blood pressure. Administration of an FGFR4-specific blocking antibody reduced cardiac hypertrophy in the 5/6 nephrectomy rat model of CKD, suggesting that pharmacological interference with myocardial FGF23/FGFR4 signaling might serve as a novel cardio-protective therapeutic approach in CKD. Here, we will study if active vitamin D (VitD) and soluble klotho (sKL), two endocrine factors with known cardio-protective functions and whose serum levels are significantly reduced in CKD, confer their anti-hypertrophic actions by blocking FGF23/FGFR4/PLC?/calcineurin/NFAT signaling in cardiac myocytes. This hypothesis is supported by our preliminary data showing that sKL and VitD block FGF23-induced hypertrophic growth of cultured cardiac myocytes.
In Aim 1, we will determine if these inhibitory actions of sKL and VitD are associated with a reduction in FGF23-induced PLC? and NFAT activity. Our preliminary work indicates that VitD inhibits the FGFR4/PLC? interaction in FGF23-stimulated cardiac myocytes, and we will study if activated VitD receptor (VDR) can directly bind PLC? and/or FGFR4 to block PLC? activation post FGF23 treatment. Klotho is a transmembrane protein that binds to FGFRs and acts as co-receptor for FGF23 in the kidney. Here, we will determine if sKL can also interact with FGF23 and/or FGFR4 thereby blocking FGF23/FGFR4 binding and subsequent PLC?/calcineurin/NFAT signaling in cardiac myocytes. It has been shown that administration of VitD or sKL in rodent models of CKD reduces cardiac hypertrophy, and our preliminary data in 5/6 nephrectomized rats indicates that VitD inhibits myocardial calcineurin/NFAT activity.
In Aim 2, we will determine if delivery of VitD or sKL can block FGFR4/PLC?/calcineurin/NFAT signaling in 5/6 nephrectomized rats and reduce cardiac hypertrophy. Furthermore, we will study if administration of VitD or sKL to an established genetic mouse model for cardiac hypertrophy induced by expression of a constitutively active FGFR4 mutant form, inhibits FGFR4/PLC?/calcineurin/NFAT signaling and improves cardiac morphology and function. We postulate that by interfering with FGF23-induced cardiac hypertrophy, administration of sKL and VitD might serve as a novel therapeutic strategy to tackle cardiac injury and death in patients with CKD.

Public Health Relevance

Cardiac hypertrophy is an important mechanism of cardiovascular disease, which is the leading cause of death of a large number of patients with chronic kidney disease (CKD). In patients with CKD, circulating levels of fibroblast growth factor 23 (FGF23) are markedly elevated, levels of active vitamin D and soluble klotho (sKL) are severely depressed, and each of these alterations contributes to cardiac hypertrophy. In this proposal, we will characterize the crosstalk between FGF23, vitamin D and sKL signaling in the heart, and test beneficial cardiac effects of a novel therapeutic approach that combines administration of vitamin D and sKL in rodent models of CKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DK115074-02
Application #
9572922
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Rankin, Tracy L
Project Start
2017-09-01
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Kogan, Daniel; Grabner, Alexander; Yanucil, Christopher et al. (2018) STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion. J Clin Invest 128:1867-1872
Grabner, Alexander; Schramm, Karla; Silswal, Neerupma et al. (2017) FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Sci Rep 7:1993