甲状旁腺素及其与水盐代谢调节因素相互作用在高血压发病中的作用及机制

Hypertension is the most important reversible risk factor for cardiovascular diseases. Parathyroid hormone (PTH),as one of the regulators of calcium and phosphate homeostasis, plays an important role in arterial calcification. Previous cross-sectional studies , including ours, demonstrated that serum PTH level was positively and independently associated with the presence of hypertension. However, up to now the causal relationship between PTH and hypertension has not been established, and the involved mechanisms remain unclear. Recent evidence suggested that PTH interacted with the renin-angiotensin-aldosterone system (RAAS). We hypothesized that increased PTH might result in hypertension via its interaction with salt intake, local RAAS in the kidney, and renal sodium-transfering proteins. In this comprehensive project, we will first analyze the prospective data of our population cohort to examine if there is a causal relationship between PTH and incidence of hypertension. We will then investigate the role of the interaction of PTH with salt intake, circulating and local renal RAAS activation, and kidney sodium handling deficiency in the pathogenesis of hypertension by carrying out cohort studies, random crossover sodium loading studies in human, and experimental animal and molecular studies. The present project will help to understand the role of PTH in the pathogenesis of hypertension, and may help in finding a novel intervention target for hypertension.

高血压是多种心血管疾病的最重要的可控危险因素。钙磷代谢调节因子甲状旁腺素（PTH）在动脉钙化中起重要作用。既往研究，包括我们课题组的横断面研究发现，PTH增高与高血压密切关联。但PTH与高血压的因果关系尚不明确，机制也不十分清楚。最新研究显示PTH和肾素-血管紧张素-醛固酮系统（RAAS）存在相互作用。我们假设PTH可能和盐摄入、肾脏局部RAAS、肾脏钠转运蛋白等水盐代谢调节因素相互作用，影响高血压发病。在本项目中，我们将利用前瞻性队列明确PTH和高血压发病的因果关系，并通过随机交叉盐负荷人体试验、动物及分子水平试验等探讨PTH与盐摄入、循环和肾脏局部RAAS激活、肾脏钠盐处理异常的关系及其在高血压发生和发展中的作用及可能的机制。课题研究结果将有助于深入了解PTH在高血压发病中的作用及机制，为高血压的防治寻找新的干预靶点。

高血压是多种心血管疾病的最重要的可控危险因素。钙磷代谢调节因子甲状旁腺素（PTH）对软组织内钙盐沉积有调控作用，PTH升高可引起血管钙化，但其与高血压及血管硬化的关系仍不明确。本课题组在既往高血压未治疗患者队列研究的基础上，进行了前瞻性随访研究以及基因学检测，证实：1、PTH与动态血压及中心动脉血压呈正相关，并且这一相关性可能有高盐负荷和醛固酮分泌增多介导。在24小时尿钠排泄升高的受试者中，PTH升高与夜间收缩压/舒张压升高显著相关（+ 4.2/3.1 mm Hg，P < 0.001）。2、在分子水平及基因水平，证实PTH与动脉硬化呈正相关，PTH每增加1倍，基线及5年随访PWV增加0.14 m/s (P=0.029)及0.20m/s (P=0.035)。PTH对动脉硬化的影响有直接作用(P=0.026)，也有通过血压介导的间接作用(P=0.043)，并且PTH基因对肌性动脉及弹性动脉硬度存在相反的作用效应。3、利用CKD+饲料高磷负荷诱导继发性甲旁亢模型，CKD组血清PTH明显高于正常对照组，并且随着饲料中磷浓度升高，PTH水平升高，颈动脉、胸动脉钙化面积上升；同时血清磷、钙磷乘积也升高，而血清维生素D、动脉维生素D受体表达降低。PTH、钙磷及维生素D可能对动脉硬化的诱导存在协同作用。课题研究结果将有助于深入了解PTH对高血压及动脉硬化的作用及机制，为心血管事件的防治寻找新的干预靶点。