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.

项目摘要慢性肾脏病（CKD）是一个公共卫生问题，可增加心血管疾病和死亡。通过促进心力衰竭，心脏肥大是CKD的重要病理，最多影响90％到患者到达透析时。骨源性成纤维细胞生长因子的血清水平升高（FGF）23是CKD的常见，早期的代谢并发症，与心血管密切相关事件和死亡率。在最近的实验研究中，我们证明在这种情况下，FGF23可能充当通过直接靶向心肌细胞和诱导心脏肥大的因果因素。我们可以证明 FGF23可以特异性激活FGF受体同工型4（FGFR4）和随后的PLCγ/钙调神经/NFAT 信号传导导致心肌细胞的肥厚性生长，这与血液中的高度无关压力。施用FGFR4特异性阻断抗体减少了5/6中的心肥大 CKD的肾切除大鼠模型，表明药物干扰了心肌FGF23/FGFR4 信号传导可能是CKD中新型的心脏保护治疗方法。在这里，我们将研究是否活跃维生素D（VITD）和固体Klotho（SKL），两个具有已知心脏保护功能的内分泌因子和 CKD中的血清水平显着降低，通过阻塞来赋予其抗肌营养作用心肌细胞中的FGF23/FGFR4/PLCγ/钙调神经/NFAT信号传导。这个假设得到了我们的支持初步数据表明SKL和VITD阻滞FGF23诱导的培养心脏的肥厚性生长心肌细胞。在AIM 1中，我们将确定SKL和VITD的这些抑制作用是否与 FGF23诱导的PLCγ和NFAT活性的降低。我们的初步工作表明VITD抑制 FGFR4/PLCγ相互作用在FGF23刺激的心肌细胞中，如果激活的VITD接收器，我们将研究（VDR）可以直接结合PLCγ和/或FGFR4，以阻止FGF23处理后的PLCγ激活。克洛托是一个跨膜蛋白与FGFR结合并充当肾脏中FGF23的共受体。在这里，我们会的确定SKL是否也可以与FGF23和/或FGFR4相互作用，从而阻止FGF23/FGFR4结合和心肌细胞中随后的PLCγ/钙调神经/NFAT信号传导。已经表明的是 CKD的啮齿动物模型中的VITD或SKL降低了心脏肥大，我们的初步数据在5/6中肾切除大鼠表明VITD抑制心肌钙调神经/NFAT活性。在AIM 2中，我们将确定VITD或SKL的递送是否可以阻止5/6 Nephrrctomized中的FGFR4/PLCγ/Clacineurin/NFAT信号传导大鼠并减少心脏肥大。此外，我们将研究是否给予VITD或SKL 由组成型活性表达诱导的心脏肥大的遗传小鼠模型 FGFR4突变体形式，抑制FGFR4/PLCγ/钙调神经/NFAT信号传导，并改善心脏形态和心脏形态和功能。我们假设通过干扰FGF23诱导的心脏肥大，SKL和给药 VITD可能是解决CKD患者心脏损伤和死亡的一种新型治疗策略。