Hyperphosphatemia Contributes to Cardiac Injury in Chronic Kidney Disease

高磷血症导致慢性肾病患者心脏损伤

基本信息

批准号：
10570845
负责人：
Isaac D Campos
金额：
$ 4.77万
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：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570845
关键词：
Adenine Anemia Animal Model Biological Markers Blood Calcineurin Cardiac Cardiac Death Cardiac Myocytes Cardiovascular Diseases Cell Surface Receptors Cells Cessation of life Chronic Kidney Failure Co-Immunoprecipitations Control Animal Development Diet Disease Drug Targeting Echocardiography Ensure Epidemic Event Fibroblast Growth Factor Receptors Fibrosis Gene Expression Genes Growth Health Heart Heart Diseases Heart Hypertrophy Heart Injuries Histologic Hormones Hypertrophy Inflammation Inflammatory Injury Inorganic Phosphate Transporter Integral Membrane Protein Kidney Knock-out Link Metabolism Minerals Mitogen-Activated Protein Kinases Modeling Molecular Molecular Analysis Morphology Mus PTH gene Pathologic Pathology Patients Positioning Attribute Production Protein Isoforms Reporting Research Proposals Risk Rodent Rodent Model Serum Severity of illness Signal Transduction Smooth Muscle Myocytes Source Structure Testing Time Tissues Tubular formation Vascular Smooth Muscle Vascular calcification Vitamin D Western Blotting Work bone calcification cell type coronary fibrosis cytokine design experimental study extracellular fibroblast growth factor 23 heart damage in vivo inorganic phosphate mortality mortality risk mouse model novel novel therapeutic intervention nuclear factors of activated T-cells osteogenic paracrine pharmacologic phospholipase C gamma premature prevent programs protein function receptor renal damage systemic inflammatory response tissue injury uptake

项目摘要

PROJECT SUMMARY Chronic kidney disease (CKD) is a health epidemic that increases risk of death due to cardiovascular disease. Hyperphosphatemia and elevations in serum levels of the hormone fibroblast growth factor (FGF) 23 are a hallmark of CKD and associated with an increased risk of cardiac injury and death. We previously found that in rodents, hyperphosphatemia induced by the administration of a high-phosphate diet elevates serum FGF23 levels and causes cardiac hypertrophy in the absence of kidney damage, suggesting that elevated phosphate and/or FGF23 per se might act as circulating factors that can damage the heart. However, whether phosphate or FGF23 can directly target the heart and induce injury is unknown. FGF23 is mainly produced by bone, and we previously found that FGF23 can activate specific signaling events in cultured cardiac myocytes and induce hypertrophy. However, whether FGF23 can directly target cardiac myocytes in vivo remains unknown. Based on global FGFR4 deletion and pharmacological FGFR4 inhibition studies, we have recently identified FGFR4 as the FGF23 receptor that is required for the development of cardiac hypertrophy in animal models of CKD as well as in mice on high-phosphate diet. For the proposed study we have generated a novel mouse model for the cardiac myocyte-specific deletion of FGFR4. By inducing CKD via an adenine diet or by administration of a high- phosphate diet, we will be able to determine whether FGF23/FGFR4 activation in the heart is required for the development of cardiac injury. Furthermore, direct effects of phosphate on cardiac myocytes have not been studied to date. Our preliminary work indicates that elevations of extracellular phosphate levels in cardiac myocyte cultures induce pro-inflammatory signaling and osteogenic gene programs. Here we will determine whether these changes lead to pathologic cardiac remodeling in mice, including cardiac hypertrophy, fibrosis, inflammation and calcification. We also found that phosphate treatments of cultured cardiac myocytes induce the expression of FGF23 that under normal conditions is not found in the heart. It has been reported that in CKD the heart starts to produce FGF23. However, whether heart-derived FGF23 can cause cardiac remodeling, is unclear. To determine the consequences of cardiac FGF23 production, we will generate a new mouse model with cardiac myocyte-specific deletion of FGF23, followed by the administration of high-phosphate or adenine diets, and a detailed analysis of cardiac structure and function. Overall, our study is designed to test the hypothesis that hyperphosphatemia - by itself as well as in the context of CKD - contributes to cardiac injury by inducing FGF23 production in the heart. FGF23 is a potent pro-hypertrophic factor, and like circulating FGF23, paracrine FGF23 might directly target cardiac myocytes via FGFR4 and induce cardiac injury. We postulate that pharmacologic blockade of FGFR4 can inhibit the pathologic actions of FGF23 on the heart and thereby serve as a novel therapeutic strategy to prevent or treat CKD-associated cardiac injury and prolong survival.

项目摘要慢性肾脏疾病（CKD）是一种健康流行病，可增加由于心血管疾病而导致死亡的风险。激素成纤维细胞生长因子（FGF）23的血清血清水平的高度和升高是A CKD的标志，与心脏损伤和死亡的风险增加有关。我们以前发现啮齿动物，高磷酸盐饮食诱导的高磷酸血症升高血清FGF23 在没有肾脏损伤的情况下，水平并引起心脏肥大，表明磷酸盐升高和/或FGF23本身可能充当会损害心脏的循环因素。但是，是否磷酸盐或FGF23可以直接靶向心脏，诱导损伤是未知的。 FGF23主要由骨骼产生，我们先前发现FGF23可以激活培养的心肌细胞中的特定信号事件并诱导肥大。但是，FGF23是否可以直接靶向体内心脏肌细胞，仍然未知。基于全球FGFR4缺失和药理学FGFR4抑制研究，我们最近确定FGFR4为 FGF23受体在CKD的动物模型以及心脏肥大以及在高磷酸盐饮食的小鼠中。对于拟议的研究，我们为心脏生成了新型的小鼠模型 FGFR4的心肌细胞特定缺失。通过腺嘌呤饮食诱导CKD或通过高磷酸盐饮食，我们将能够确定是否需要心脏中的FGF23/FGFR4激活心脏损伤的发展。此外，磷酸盐对心肌细胞的直接影响尚未迄今为止研究了。我们的初步工作表明心脏细胞外磷酸盐水平的升高肌细胞培养物诱导促炎性信号传导和成骨基因程序。在这里我们将确定这些变化是否导致小鼠的病理心脏重塑，包括心脏肥大，纤维化，炎症和钙化。我们还发现培养的心肌细胞的磷酸盐治疗诱导在心脏中找不到正常条件下FGF23的表达。据报道，在CKD中心脏开始产生FGF23。但是，心脏来源的FGF23是否会引起心脏重塑，是不清楚。为了确定心脏FGF23产生的后果，我们将生成新的鼠标模型具有FGF23的心肌细胞特异性缺失，然后使用高磷酸盐或腺嘌呤饮食，以及心脏结构和功能的详细分析。总体而言，我们的研究旨在测试假设高磷酸血症本身以及在CKD的背景下都导致心脏损伤心脏中诱导FGF23产生。 FGF23是一种有效的亲脑性因素，就像循环FGF23一样，旁分泌FGF23可能通过FGFR4直接靶向心肌细胞并诱导心脏损伤。我们假设 FGFR4的药物阻滞可以抑制FGF23在心脏上的病理作用，从而抑制作为预防或治疗与CKD相关的心脏损伤和延长生存期的新型治疗策略。