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.
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.
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