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

维生素 D 和可溶性 Klotho 抑制慢性肾病中 FGF23 介导的心脏肥大

基本信息

批准号：
9396739
负责人：
Christopher Yanucil
金额：
$ 3.48万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9396739
关键词：
Affect Agonist Animal Model Attenuated Binding Binding Proteins Blocking Antibodies Blood Pressure Calcineurin Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cause of Death Cells Cessation of life Chronic Kidney Failure Clinical Complex Complication Data Depressed mood Dialysis procedure Dihydroxycholecalciferols Echocardiography Endocrine Event Excretory function Fibroblast Growth Factor Receptors Genetic Growth Heart Heart Block Heart Hypertrophy Heart failure Histology Hormones Hypertrophy Impairment Injectable Injury Integral Membrane Protein Kidney Knock-in Mouse Mediating Membrane Metabolic Mitogen-Activated Protein Kinases Modeling Molecular Morphology Mus Mutation Myocardial Nephrectomy Outcome Pathologic Pathology Patients Pharmacology Production Protein Isoforms Public Health Rattus Renal Mass Reporting Rodent Rodent Model Serum Signal Transduction Testing Therapeutic Time Tissues Ventricular Remodeling Vitamin D Vitamin D3 Receptor Work bone cardiovascular disorder risk coronary fibrosis disorder risk experimental study fibroblast growth factor 23 fibroblast growth factor receptor 4 functional loss improved inorganic phosphate mortality mouse model mutant novel novel therapeutic intervention novel therapeutics nuclear factors of activated T-cells phospholipase C gamma pressure protective effect receptor

项目摘要

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.

项目总结