Vitamin D Deficiency Augments Renin-Angiotensin System Activity in Obesity

描述（由申请人提供）：本研究的总体目的是研究补充维生素D是否会降低肥胖患者内源性肾素-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，这使它们成为美国乃至全世界人类发病和死亡的最重要的可逆原因。与肥胖高血压发病机制相关的主要机制是RAS活性失调；因此，有效的方法来调节肥胖中的RAS可能对预防健康有巨大的意义。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。初步数据显示，肥胖内源性RAS活性可以通过血管对外源性血管紧张素II （AngII）输注的反应来量化。具体目标：维生素D缺乏增加内源性RAS活性；测量为钝化血压（BP）和肾血流（RBF）对AngII的反应。补充维生素D可以改善BP （Aim 1）和RBF （Aim 2）对AngII的反应，这与内源性RAS活性降低的效果类似于ACE抑制剂（Aim 3）。研究设计：16名高血压和维生素D缺乏症的肥胖高危人群将进行一项干预性先导研究，设计为补充维生素D的前瞻性队列。方法：为了尽量减少环境因素对RAS的影响，所有受试者将停用任何干扰RAS的药物，并保持饮食中钠、钾和钙的平衡。然后，在补充维生素D前后，受试者将接受住院治疗，以测量RAS循环成分及其血管对外源性AngII的敏感性（以BP和RBF测量）。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）前后进行测量。补充维生素D后，预计血管对AngII的敏感性将显著改善，与卡托普利后的血管敏感性相当。意义：证明维生素D可以有利地调节血管对AngII的敏感性，这将为肥胖患者缺乏维生素D会放大RAS，而补充维生素D会抑制RAS的假设提供实质性的证据。补充维生素D可能是一种廉价、容易获得的生理性干预措施，可以降低这一人群的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.