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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL104776-02
Application #
8224239
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Carlson, Drew E
Project Start
2010-07-16
Project End
2012-02-28
Budget Start
2011-07-16
Budget End
2012-02-28
Support Year
2
Fiscal Year
2011
Total Cost
$42,050
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Vaidya, Anand; Underwood, Patricia C; Annes, Justin P et al. (2013) The influence of sodium- and calcium-regulatory hormone interventions on adipocytokines in obesity and diabetes. Metabolism 62:539-47
Vaidya, Anand; Sun, Bei; Larson, Carol et al. (2012) Vitamin D3 therapy corrects the tissue sensitivity to angiotensin ii akin to the action of a converting enzyme inhibitor in obese hypertensives: an interventional study. J Clin Endocrinol Metab 97:2456-65
Vaidya, Anand; Williams, Jonathan S (2012) The relationship between vitamin D and the renin-angiotensin system in the pathophysiology of hypertension, kidney disease, and diabetes. Metabolism 61:450-8
Vaidya, Anand; Williams, Jonathan S (2012) Vitamin D and insulin sensitivity: can gene association and pharmacogenetic studies of the vitamin D receptor provide clarity? Metabolism 61:759-61
Vaidya, Anand; Hurwitz, Shelley; Yialamas, Maria et al. (2012) Improving the management of diabetes in hospitalized patients: the results of a computer-based house staff training program. Diabetes Technol Ther 14:610-8
Vaidya, Anand; Forman, John P (2012) Vitamin D and vascular disease: the current and future status of vitamin D therapy in hypertension and kidney disease. Curr Hypertens Rep 14:111-9
Min, Le; Vaidya, Anand; Becker, Carolyn (2012) Association of ipilimumab therapy for advanced melanoma with secondary adrenal insufficiency: a case series. Endocr Pract 18:351-5
Larson, Carol; Vaidya, Anand; Sun, Bei et al. (2012) Influence of dietary sodium modulation on electrocardiographic voltage criteria for left ventricular hypertrophy in normotensive individuals. J Investig Med 60:39-43
Vaidya, Anand; Williams, Jonathan S; Forman, John P (2012) The independent association between 25-hydroxyvitamin D and adiponectin and its relation with BMI in two large cohorts: the NHS and the HPFS. Obesity (Silver Spring) 20:186-91
Underwood, Patricia C; Chamarthi, Bindu; Williams, Jonathan S et al. (2012) Replication and meta-analysis of the gene-environment interaction between body mass index and the interleukin-6 promoter polymorphism with higher insulin resistance. Metabolism 61:667-71

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