Vitamin D Deficiency Augments Renin-Angiotensin System Activity in Obesity

描述(申请人提供)：这项研究的总体目标是检查补充维生素D是否能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导致人类发病率和死亡率的最重要的可逆原因。RAS活性失调是肥胖症高血压发病的主要机制之一，因此，有效地调控肥胖患者RAS的活性可能对预防健康具有重要意义。最近的动物研究表明维生素D是RAS的抑制剂；然而，缺乏人类研究。初步数据显示，肥胖患者的内源性RAS活性可以通过血管对外源性血管紧张素II(AngII)注射的反应来量化。具体目标：维生素D缺乏增加内源性RAS活性；测量为对血管紧张素转换酶抑制的血压(BP)和肾血流量(RBF)的反应。补充维生素D可改善BP(Aim 1)和RBF(Aim 2)对血管紧张素转换酶II的反应，与内源性RAS活性降低一致，类似于ACE抑制剂的效果(Aim 3)。研究设计：16名患有高血压和维生素D缺乏的肥胖高危人群将接受一项干预性先导研究，作为补充维生素D的前瞻性队列研究。方法：为了最大限度地减少环境对RAS的影响，所有受试者都将被淘汰掉任何干扰RAS的药物，并保持饮食中的钠、钾和钙平衡。然后，受试者将在补充维生素D的四周之前和之后接受住院治疗，以测量RAS的循环成分和他们对外源性血管紧张素转换酶的血管敏感性(测量血压和RBF)。还将在急性服用血管紧张素转换酶抑制剂卡托普利前后测量血管对血管紧张素转换酶抑制剂的敏感性。在补充维生素D后，预计血管对血管紧张素转换酶的敏感性将显著改善，与卡托普利的血管敏感性相当。意义：证明维生素D可以有利地调节血管对血管紧张素转换酶的敏感性，这将为肥胖时维生素D缺乏会放大RAS，而补充维生素D则会抑制RAS的假说提供充分的证据。补充维生素D可能是一种廉价、容易获得的生理干预措施，可以降低这一人群中的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。RAS的过度活动被认为是心血管疾病的诱因；因此，逆转肥胖患者的维生素D缺乏在预防心血管风险方面可能具有重大的公共卫生意义。该项目旨在研究在肥胖患者中补充维生素D是否会降低人类的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.