Changes in phosphate metabolism cause pathologic cardiac remodeling in chronic kidney disease (CKD)

磷酸盐代谢的变化导致慢性肾病（CKD）的病理性心脏重塑

• 批准号: 10343728
• 负责人: Christian Faul
• 金额: $ 58.49万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343728
• 关键词: Adenine; Agonist; Animal Model; Attenuated; Binding; Bone Diseases; Calcineurin; Cardiac; Cardiac Myocytes; Cardiac development; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic Kidney Failure; Clinical; Clinical Research; Data; Dependovirus; Diet; Dihydroxycholecalciferols; Disease; Echocardiography; Endocrine; Excretory function; FGFR4 gene; Fibroblast Growth Factor Receptors; Growth; Heart; Heart Hypertrophy; Heart Injuries; Hepatic; Histology; Homeostasis; Hormones; Hypertrophy; Impairment; Infusion procedures; Integral Membrane Protein; Intervention; Kidney; Knock-in Mouse; Lead; Mediating; Mendelian disorder; Metabolism; Minerals; Modeling; Molecular; Mus; Mutation; Myocardial dysfunction; Nephrectomy; Outcome; Pathologic; Patients; Pharmacology; Phospholipase C; Production; Protein Isoforms; Proteolysis; Publishing; Rattus; Recombinants; Regimen; Renal Mass; Reporting; Rodent; Rodent Model; Serum; Signal Pathway; Signal Transduction; Stimulus; System; T-Cell Activation; Therapeutic; Tissues; Ventricular Remodeling; Vitamin D; Vitamin D3 Receptor; Work; bone; cardioprotection; coronary fibrosis; experimental study; fibroblast growth factor 23; fibroblast growth factor receptor 4; functional loss; in vivo; inorganic phosphate; loss of function; mortality; mouse model; novel; nuclear factors of activated T-cells; osmotic minipump; protective effect; receptor; tissue injury; vitamin receptor

ABSTRACT Fibroblast growth factor (FGF) 23 is a bone-derived hormone that targets the kidney via FGF receptors (FGFR) and klotho, a transmembrane protein (‘mKL’) that acts as an FGF23 co-receptor, thereby increasing renal phosphate excretion and lowering serum phosphate levels. In patients with chronic kidney disease (CKD), FGF23-responsiveness and phosphate reabsorption are impaired, leading to increased serum phosphate concentrations and FGF23 production in bone. Clinical studies have shown that elevated serum FGF23 levels are strongly associated with negative outcomes in CKD, such as cardiac hypertrophy and cardiovascular mortality. Our translational work indicates that circulating FGF23 can directly contribute to tissue injury that is associated with CKD. By activating FGF receptor (FGFR) 4 and subsequent phospholipase C (PLC)/calcineurin/nuclear factor of activated T cells (NFAT) signaling in cardiac myocytes, FGF23 induces cardiac hypertrophy and fibrosis in rodents. This pathologic effect occurs independently of klotho that is not expressed in the heart. Klotho also exists in a truncated soluble form (‘sKL’) that is generated by proteolysis of mKL and released from the kidney. Experimental studies indicate that sKL has tissue-protective effects, including anti-hypertrophic and anti-fibrotic actions in the heart, similar to active vitamin D (‘1,25D‘), which also acts as a cardio-protective hormone. In patients with CKD, serum levels of sKL and 1,25D are significantly reduced, and it is thought that a loss of sKL’s and 1,25D’s protective effects contributes to CKD-associated tissue injury. Since our published and preliminary work indicates that sKL and 1,25D can inhibit FGF23-induced signaling and hypertrophy in cultured cardiac myocytes, we hypothesize that sKL and 1,25D attenuate pathologic actions of FGF23 in the heart. In Aim 1, we will study in mice on an adenine-rich diet (AD), a model for CKD with high FGF23 that develops cardiac hypertrophy, whether systemic sKL elevations by AAV delivery attenuate cardiac hypertrophy, and vise-versa, whether the absence of sKL in a mouse model with kidney-specific klotho deletion accelartes cardiac injury. In isolated cardiac myocytes, we will study the mechanism underlying sKL’s anti- hypertrophic effects and determine if by interacting with FGF23, sKL can block FGF23 binding to FGFR4 and/or FGFR4 activation. In Aim 2, we will determine if administration of 1,25D has cardio-protective effects in mice on AD, as well as in genetically modified mice with constitutive FGFR4 activation and cardiac hypertrophy. We will also study if in mice with cardiac-specific deletion of the vitamin receptor (VDR) which spontaneously develop cardiac hypertrophy, the elevation of serum FGF23 levels by AD or by osmotic minipump infusions of recombinant FGF23 aggravates cardiac injury. We postulate that via the studied mechanism, elevated serum FGF23, and reduced serum levels of sKL and 1,25D, three clinical hallmarks of CKD, synergistically contribute to CKD-associated cardiac injury. A combination of pharmacological interventions activating VDR, elevating circulating sKL and blocking FGF23/FGFR4 signaling might have cardio-protective effects in patients with CKD.

摘要 成纤维细胞生长因子（FGF）23是一种骨源性激素，通过FGF受体（FGFR）靶向肾脏。 和klotho，一种跨膜蛋白（“mKL”），其充当FGF 23共受体，从而增加肾功能。 磷酸盐排泄和降低血清磷酸盐水平。在慢性肾病（CKD）患者中， FGF 23反应性和磷酸盐重吸收受损，导致血清磷酸盐升高 骨中的浓度和FGF 23产生。临床研究表明，血清FGF 23水平升高 与CKD的不良结局密切相关，如心脏肥大和心血管疾病 mortality.我们的翻译工作表明，循环中的FGF 23可以直接导致组织损伤， 与CKD有关。通过激活FGF受体（FGFR）4和随后的磷脂酶C β (PLC在心肌细胞中，FGF 23诱导活化T细胞的核因子（NFAT）/钙调神经磷酸酶/核因子（NFAT）信号传导， 心脏肥大和纤维化。这种病理效应的发生独立于klotho， 表达在心中。Klotho也以截短的可溶形式（“sKL”）存在，其通过蛋白水解 mKL并从肾脏释放。实验研究表明，sKL具有组织保护作用，包括 抗心脏肥大和抗纤维化作用，类似于活性维生素D（“1，25 D”），也可作为 心脏保护激素在CKD患者中，血清sKL和1，25 D水平显著降低， 人们认为sKL和1，25 D保护作用的丧失导致CKD相关的组织损伤。以来 我们已发表的和初步的工作表明，sKL和1，25 D可以抑制FGF 23诱导的信号传导， 我们推测sKL和1，25 D能减轻心肌细胞肥大的病理作用， 心脏中的FGF 23在目标1中，我们将在小鼠中研究富含腺嘌呤的饮食（AD），这是一种高表达的CKD模型。 通过AAV递送的全身性sKL升高是否会减弱心脏肥大， 肥大，反之亦然，在具有肾特异性klotho缺失的小鼠模型中是否缺乏sKL 加速心脏损伤。在离体心肌细胞中，我们将研究sKL抗心肌细胞凋亡的机制。 肥大作用，并确定通过与FGF 23相互作用，sKL是否可以阻断FGF 23与FGFR 4的结合和/或 FGFR 4激活。在目标2中，我们将确定1，25 D的给药是否对小鼠的心脏具有保护作用， AD，以及具有组成性FGFR 4活化和心脏肥大的遗传修饰小鼠。我们将 还研究了心脏特异性维生素受体（VDR）缺失的小鼠， 心脏肥大，AD或渗透性微型泵输注导致血清FGF 23水平升高 重组FGF 23减轻心脏损伤。我们推测，通过研究的机制，血清中 FGF 23和sKL和1，25 D的血清水平降低（CKD的三个临床标志）协同促进 CKD相关的心脏损伤。结合药物干预激活VDR，提高 循环sKL和阻断FGF 23/FGFR 4信号传导可能对CKD患者具有心脏保护作用。