Vitamin D Deficiency Augments Renin-Angiotensin System Activity in Obesity

描述（由申请方提供）：本研究的总体目的是检查补充维生素D是否降低肥胖患者的内源性肾素-血管紧张素系统活性（RAS）。肥胖和高血压之间的联系是不可否认的，这使得它们可以说是美国和世界范围内人类发病率和死亡率最重要的可逆原因。肥胖症高血压发病机制中涉及的主要机制是RAS活性失调;因此，调节肥胖症RAS的有效方法可能对预防性健康具有巨大意义。最近的动物研究表明维生素D是RAS的抑制剂;然而，缺乏人体研究。初步数据表明，内源性RAS活动在肥胖症可以量化使用血管反应外源性血管紧张素II（AngII）输注。具体目标：维生素D缺乏会增加内源性RAS活性;测量为对AngII的钝性血压（BP）和肾血流量（RBF）反应。补充维生素D改善了BP（目的1）和RBF（目的2）对AngII的反应，与ACE抑制剂（目的3）的作用类似的内源性RAS活性降低一致。研究设计：16名患有高血压和维生素D缺乏症的肥胖受试者的高风险人群将进行干预性初步研究，设计为补充维生素D的前瞻性队列。研究方法：为了尽量减少环境对RAS的影响，所有受试者将被清除任何干扰RAS的药物，并维持饮食中的钠、钾和钙平衡。然后，受试者将在补充维生素D四周前后住院，以测量RAS的循环组分及其对外源性AngII的血管敏感性（测量为BP和RBF）。血管对AngII的敏感性也将在急性给药卡托普利（一种ACE抑制剂）之前和之后测量。在补充维生素D后，预期血管对AngII的敏感性将显著改善，并且与卡托普利后的血管敏感性相当。重要性：证明维生素D可以有利地调节血管对AngII的敏感性，这将为肥胖症中维生素D缺乏症放大RAS的假设提供实质性的证据，而补充维生素D则会抑制RAS。补充维生素D可能代表一种廉价、易得的生理干预措施，以降低该人群中的RAS活性。 公共卫生相关性：肥胖和维生素D缺乏是已知同时存在的流行性疾病，最近的证据表明这两种疾病都与肾素-血管紧张素系统（RAS）活性增加有关。已知RAS的过度活动会导致心血管疾病;因此，逆转肥胖症中的维生素D缺乏可能对预防心血管风险具有重大的公共卫生意义。该项目旨在研究肥胖症患者补充维生素D是否会降低人体RAS活性。

DESCRIPTION (provided by applicant): The overall aim of this study is to examine whether Vitamin D supplementation reduces endogenous renin-angiotensin system activity (RAS) in obesity. The link between obesity and hypertension is undeniable, making them arguably the most important reversible causes of human morbidity and mortality in the U.S. and worldwide. A major mechanism implicated in the pathogenesis of hypertension in obesity is dysregulated activity of the RAS; thus, effective methods to regulate the RAS in obesity may have tremendous implications in preventative health. Recent animal studies have shown Vitamin D to be an inhibitor of the RAS; however, human studies are lacking. Preliminary data have shown that endogenous RAS activity in obesity can be quantified using the vascular response to exogenous angiotensin II (AngII) infusion. Specific Aims: Vitamin D deficiency increases endogenous RAS activity; measured as a blunted blood pressure (BP) and renal blood flow (RBF) response to AngII. Supplementation of Vitamin D improves the BP (Aim 1) and RBF (Aim 2) response to AngII, consistent with diminished endogenous RAS activity akin to the effect of ACE inhibitors (Aim 3). Study Design: A high-risk population of sixteen obese subjects with hypertension and Vitamin D deficiency will undergo an interventional pilot study, designed as a prospective cohort with Vitamin D supplementation. Methods: To minimize confounding by environmental influences on the RAS, all subjects will be washed-out of any medications that interfere with the RAS, and maintained in dietary sodium, potassium, and calcium balance. Subjects will then undergo hospital admission to measure circulating components of the RAS and their vascular sensitivity to exogenous AngII (measured as BP and RBF), before and after four weeks of Vitamin D supplementation. The vascular sensitivity to AngII will also be measured before and after acute dosing of captopril, an ACE inhibitor. Following Vitamin D supplementation, it is anticipated that the vascular sensitivity to AngII will be significantly improved, and comparable to the vascular sensitivity following captopril. Significance: Demonstrating that Vitamin D can favorably modulate the vascular sensitivity to AngII will provide substantial credence to the hypothesis that Vitamin D deficiency in obesity amplifies the RAS, while its supplementation subdues it. Vitamin D supplementation could represent a cheap, easily available, physiologic intervention to reduce RAS activity in this population. PUBLIC HEALTH RELEVANCE: Obesity and Vitamin D deficiency are epidemic disorders known to exist in tandem, with recent evidence implicating both disorders with increased activity of the renin-angiotensin system (RAS). Overactivity of the RAS is known to contribute to cardiovascular disease; thus, reversal of Vitamin D deficiency in obesity could have significant public health implications in preventing cardiovascular risk. This project aims to examine whether Vitamin D supplementation in obesity reduces RAS activity in humans.