Preventing Hypertension and Sympathetic Overactivation by Targeting Phosphate

通过磷酸盐预防高血压和交感神经过度激活

• 批准号: 9309263
• 负责人: SCOTT A SMITH
• 金额: $ 79.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9309263
• 关键词: Address; Aerobic Exercise; American diet; Animals; Attention; Attenuated; Blood Pressure; Brain; Brain Stem; Cardiovascular system; Cartoons; Cell Nucleus; Cerebrospinal Fluid; Chemicals; Chronic Kidney Failure; Color; Complex; Consumption; Data; Decerebration procedure; Diet; Down-Regulation; Enhancers; Excision; Exercise; Fibroblast Growth Factor Receptors; Food Industry; General Population; Health Policy; Homeostasis; Hormones; Hour; Human; Hypertension; Intake; Investigation; Isometric Exercise; Kidney; Kidney Failure; Label; Laboratories; Lead; Left Ventricular Hypertrophy; Measures; Mediating; Mus; Muscle Contraction; Nerve; Neuraxis; Nitric Oxide; Nitric Oxide Synthase Type I; Nutritional; Organ; Outcome; Patients; Play; Prevention; Production; Prosencephalon; Proteins; Public Health; Rattus; Recommended Daily Allowances; Regulation; Renal function; Rest; Risk Factors; Rodent; Rodent Model; Role; Site; Sodium; Sprague-Dawley Rats; Stress; Stretching; Sympathetic Nervous System; Techniques; Training; Translating; Vascular calcification; Work; blood pressure regulation; clinical practice; coronary fibrosis; exercise training; fibroblast growth factor 23; high risk population; hypertension prevention; hypertension treatment; innovation; inorganic phosphate; modifiable risk; mortality; neuroregulation; normotensive; novel; prehypertension; prevent; restoration; translational study

Project Summary Inorganic phosphates (Pi) are widely used in the food industry as preservatives. High Phosphate (Pi) intake is a well-recognized contributor to vascular calcification and cardiovascular mortality in patients with renal failure. More recently, a high Pi diet was shown to trigger BP elevation even in rodents with normal kidneys. Mechanisms underlying detrimental effects of high Pi diet are complex and largely unknown but our recent study in rats have identified novel mechanisms mediating Pi-induced hypertension (HTN) and left ventricular hypertrophy via overactivation of the sympathetic nervous system. Our data also suggest that animals fed a high Pi but constant sodium intake have an elevated cerebrospinal fluid content of fibroblast growth factor 23 (FGF23, a key hormone in Pi homeostasis), and reduced expression within the central nervous system (CNS) of Klotho (a key protein in Pi homeostasis). Klotho has also been shown to increase nitric oxide (NO) production in the vasculature. In the CNS, it has been established that NO produced by the neuronal form of nitric oxide synthase (nNOS) plays a major inhibitory role on central sympathetic outflow. Klotho expression was shown to increase after regular exercise in mice and humans. However, the role of dietary Pi, Klotho, and FGF23 in the neural control of blood pressure (BP) has not been investigated. Thus, we propose parallel translational studies in normal rats and prehypertensive humans (BP 120-129/80-84 mmHg) to systematically investigate the influence of dietary Pi on sympathetic nervous system and BP regulation. The proposed studies are innovative in that they maintain the potential to shift current clinical practice paradigms by identifying phosphate as a key modifiable risk factor for the prevention and treatment of hypertension. The ultimate results of our work could lead to more effective strategy in reducing the global burden of hypertension and target organ complications. We envision this work advancing the field in several important ways: (1) translating work from rodent models to human hypertension, using of the state-of-the-art techniques of microneurography; (2) examining the role of dietary phosphate in neural control of BP both at rest and during exercise, which has not been previously addressed; (3) demonstrating the role of inorganic phosphate in regulating BP via alteration in the concentration of soluble klotho or FGF23 in the central nervous system, (4). Establishing a new role of exercise training in preventing phosphate-induced sympathetic overactivation and hypertension, and (5). Establishing a novel role of FGF receptor in the central nervous system in mediating phosphate- induced hypertension.

项目概要 无机磷酸盐（Pi）作为防腐剂广泛应用于食品工业。高磷酸盐 (Pi) 摄入量是 公认的导致肾衰竭患者血管钙化和心血管死亡的因素。 最近，研究表明，即使在肾脏正常的啮齿动物中，高 Pi 饮食也会引发血压升高。 高 Pi 饮食有害影响的机制很复杂，而且很大程度上未知，但我们最近的研究 对大鼠的研究发现了介导 Pi 诱导的高血压 (HTN) 和左心室的新机制 交感神经系统过度激活导致肥大。我们的数据还表明，动物喂食 高 Pi 但持续摄入钠会导致脑脊液中成纤维细胞生长因子 23 的含量升高 （FGF23，Pi 稳态的关键激素），以及中枢神经系统 (CNS) 内的表达减少 Klotho（Pi 稳态的关键蛋白）。 Klotho 还被证明可以增加一氧化氮 (NO) 脉管系统中的产生。在中枢神经系统中，已经确定，NO 由神经元形式产生 一氧化氮合酶（nNOS）对中枢交感神经流出起着主要的抑制作用。克洛托表达式 在小鼠和人类中进行定期锻炼后，该值会有所增加。然而，饮食中 Pi、Klotho 和 FGF23 在血压 (BP) 神经控制中的作用尚未得到研究。因此，我们提出并行 在正常大鼠和高血压前期人类（BP 120-129/80-84 mmHg）中进行的系统性转化研究 研究膳食Pi对交感神经系统和血压调节的影响。拟议的研究 创新之处在于它们通过识别来保持改变当前临床实践范式的潜力 磷酸盐作为预防和治疗高血压的关键可改变危险因素。终极 我们的工作成果可能会导致制定更有效的战略，以减轻全球高血压和高血压的负担 靶器官并发症。我们预计这项工作将在几个重要方面推动该领域的发展：（1）翻译 使用最先进的显微神经造影技术，从啮齿动物模型到人类高血压； (2) 研究膳食磷酸盐在休息和运动期间血压神经控制中的作用， 以前没有被解决过； (3)通过证明无机磷酸盐调节血压的作用 中枢神经系统中可溶性 klotho 或 FGF23 浓度的变化，(4)。建立一个 运动训练在预防磷酸盐引起的交感神经过度激活和高血压方面的新作用， 和（5）。建立 FGF 受体在中枢神经系统中介导磷酸盐的新作用 诱发高血压。