Preventing Hypertension and Sympathetic Overactivation by Targeting Phosphate

项目摘要 无机磷酸盐(PI)在食品工业中被广泛用作防腐剂。高磷酸盐(PI)摄入是 公认的肾衰竭患者血管钙化和心血管死亡率的贡献者。 最近，高PI饮食被证明即使在肾脏正常的啮齿类动物中也会引发血压升高。 高PI饮食有害影响的潜在机制是复杂的，而且很大程度上是未知的，但我们最近 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 由于交感神经系统过度激活而导致的肥大。我们的数据还表明，喂食一种 高PI但恒定钠摄入量增加脑脊液中成纤维细胞生长因子23的含量 (FGF23，PI稳态的关键激素)，并减少在中枢神经系统(CNS)的表达 Klotho(PI动态平衡的关键蛋白)。Klotho也被证明可以增加一氧化氮(NO)。 在维管系统中产生。在中枢神经系统中，已经证实NO是由神经元形式的 一氧化氮合酶(NNOS)对中枢性交感神经流出具有重要的抑制作用。Klotho表情 有研究表明，在老鼠和人类进行定期锻炼后，这一比例会增加。然而，膳食PI、Klotho和 FGF23在血压神经控制中的作用尚未见报道。因此，我们建议并行 正常大鼠和高血压前期人群(血压120-129/80-84毫米汞柱)的系统翻译研究 研究日粮PI对交感神经系统和血压调节的影响。建议进行的研究 具有创新性，因为它们保持了通过确定 磷酸盐是预防和治疗高血压的一个关键的可改变的危险因素。终极的 我们的工作结果可能导致更有效的战略，以减轻全球高血压负担和 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 从啮齿动物模型到人类高血压，使用最先进的显微神经学技术； (2)研究膳食磷酸盐在安静和运动时血压神经控制中的作用。 (3)展示了无机磷在调节血压中的作用 中枢神经系统中可溶性Klotho或FGF23浓度的变化；建立一个 运动训练在预防磷酸盐诱导的交感神经过度激活和高血压中的新作用 和(5)。在中枢神经系统中建立成纤维细胞生长因子受体在调节磷酸盐中的新作用 诱发性高血压。

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.