DESCRIPTION (provided by applicant): Aldosterone is the main mineralocorticoid hormone involved in maintaining fluid and electrolyte (sodium) balance in the human body. However, abnormalities in aldosterone production and secretion from the adrenal gland result in and/or exacerbate several human diseases including high blood pressure and congestive heart failure. These disorders are prevalent in the veteran population, with nearly 3.5 million veterans diagnosed with hypertension and approximately 10% of these with congestive heart failure. Similarly, many veterans are overweight or obese, with the attendant disorders associated with excess weight, including hypertension. The mechanism by which excess weight causes hypertension is unclear; however, some studies have suggested a link with increased aldosterone levels. Our recent novel results demonstrate that physiological concentrations of very-low-density lipoprotein (VLDL) stimulate aldosterone production in multiple zona glomerulosa cell models in vitro. This result suggests a possible mechanism by which obesity, which is associated with elevated VLDL levels (dyslipidemia), can result in hypertension resulting, at least in part, from inappropriate aldosterone secretion. To increase our understanding of the mechanisms underlying VLDL-induced aldosterone production, three specific aims are proposed in this study: (1) test the hypothesis that physiological and pathophysiological VLDL concentrations will enhance the response to other physiological stimulators of aldosterone production and determine the signaling mechanisms involved in the stimulatory action of VLDL, (2) test the hypothesis that a lipid component of VLDL elicits aldosterone secretion and define this active component, and (3) test the hypothesis that ablation of the gene encoding phospholipase D2 (PLD2), an important signal mediating aldosterone production in vitro, also regulates aldosterone levels in vivo, basally and with elevated VLDL levels related to diet-induced obesity. These hypotheses will be tested by monitoring aldosterone production in glomerulosa cell models treated with various concentrations of VLDL and other aldosterone agonists. In addition, the signal transduction mechanisms utilized by VLDL will be defined using overexpression and RNA interference-mediated knock down strategies to influence the levels of signaling molecules followed by a determination of the effect of these manipulations on VLDL-induced aldosterone production. Pretreatment to denature/degrade the protein and extraction of the lipids comprising VLDL, as well as lipidomics to identify VLDL lipid components, will be used to determine the agent in VLDL responsible for stimulating aldosterone production. The role of this VLDL component will be verified in studies determining the aldosterone stimulatory effect of VLDL pretreated using enrichment and depletion strategies to alter levels of the identified active agent. In vivo a PLD2 knockout mouse model will be used to determine the effects of the loss of PLD2 on aldosterone levels and aldosterone synthase (CYP11B2) expression in the adrenal basally and upon chronic angiotensin II infusion or with diet-induced obesity. The proposed studies examining the ability of VLDL to modulate aldosterone production will expand our knowledge of the role of obesity-increased VLDL levels in the development of hypertension in obese and/or lean individuals, as well as the possible involvement of abnormalities in the VLDL-activated signals in hypertension in these individuals.
|Effective start/end date||10/1/12 → 9/30/16|