Vitamin D and soluble Klotho inhibit FGF23-mediated cardiac hypertrophy in Chronic Kidney Disease

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PROJECT SUMMARY 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 PLCγ/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/PLCγ/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 PLCγ and NFAT activity. Our preliminary work indicates that VitD inhibits the FGFR4/PLCγ interaction in FGF23-stimulated cardiac myocytes, and we will study if activated VitD receptor (VDR) can directly bind PLCγ and/or FGFR4 to block PLCγ 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 PLCγ/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/PLCγ/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/PLCγ/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.