Primary Aldosteronism (PA) is the most common form of secondary hypertension, affecting 4-14% of those with high blood pressure. PA is associated with a significantly greater increase in cardiovascular and cerebrovascular than patients with essential hypertension with a similar increase and duration of hypertension. Two pathological diagnoses comprise about 98% PA: Idiopathic hyperaldosteronism (IHA) characterized by increased aldosterone synthesis by both adrenals and responsible for 30-70% of PA, and benign aldosterone- producing adenomas (APA). While several gene mutations have been identified in APAs, the cause of IHA is unknown. Neither genetic changes nor changes in known aldosterone (aldo) stimulating factors have been found in IHA patients. We propose to address the following hypothesis: "Idiopathic hyperaldosteronism is in part neurally mediated" and "neural modulation of aldosterone biosynthesis is important and can be explored in surrogate animals." This translational proposal will use human adrenal samples, a human adrenal cortical cell line in culture, and rat models as surrogates to tease out possible mechanisms for IHA. Chronic low sodium maximally stimulates zona glomerulosa growth and aldo synthesis. Acute sodium repletion rapidly suppresses aldo release before the disappearance of rate-limiting enzymes for its synthesis.
Specific Aim 1 will characterize the role of adrenal zona glomerulosa innervation from the adrenal medulla and capsule in the regulation of aldosterone secretion and zona glomerulosa remodeling. Rats with intact adrenals, enucleated in situ (medulla and much of the zonas reticularis/fasciculata removed, remaining neural connections to the capsule intact) and enucleated adrenals transplanted into the axilla will be studied after chronic low sodium intake followed by acute voluntary sodium replenishment to distinguish between humoral and neural control. The hypothesis that somatostatin synthesized within the adrenal medulla mediates adrenal suppression upon sodium repletion will be tested. Adrenals of adult humans have clusters of cells that express aldosterone synthase (CYP11B2 enzyme) abundantly amid quiescent ZG cells called aldosterone-producing cell clusters (APCC). Rats on a chronic high salt diet have similar APCC. Exposure to multiple cycles of chronic low sodium intake followed by sodium repletion will be studied to determine if these APCC become larger and/or aldo production becomes autonomous, leading to an IHC phenotype including hypertension in the rats. Transcriptome studies of zona glomerulosa samples of rats on a high sodium diet dissected by laser capture microdissection. Samples rich in clusters of cells expressing high levels of the aldosterone synthase will be compared with quiescent areas. Primary tools will be the measurement of the expression of steroids and genes involved in the control of steroidogenesis, including neurotransmitters know to be present in the adrenal cortex, and immunohistochemistry. We will also study the intrinsic innervation and expression of neuropeptides and receptors, as well as factors discovered in the RNAseq transcriptome studies, in normal human adrenals and those from patients with APA and IHA and correlate our findings from the human subjects with those of the rat models.
The aim i s to discover how aldosterone synthesis is actively suppressed under normal conditions and whether these mechanisms are defective in IHA and in the adrenal glomerulosa tissues surrounding the adenoma in APA which is often active despite high aldosterone and low renin/angiotensin levels.

Public Health Relevance

Hypertension is the most common cardiovascular disorder in adults. Primary aldosteronism is the most common cause of secondary hypertension and it is associated with more severe cardiovascular disease than most hypertension. More than half of PA is caused by bilateral zona glomerulosa hyperplasia of unknown cause. We propose to test the hypothesis that the increased aldosterone production in these patients is mediated by abnormal neural control with a translational approach using a dietary modification in rats, genetically modified mice, a human adrenal cortex cell line, and human adrenal specimens.

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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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OH, Youngsuk
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University of Mississippi Medical Center
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Gomez-Sanchez, Celso E (2014) Channels and pumps in aldosterone-producing adenomas. J Clin Endocrinol Metab 99:1152-6
Gomez-Sanchez, Celso E (2014) Primary aldosteronism: a channelopathy? Hypertension 63:668-9
Kem, David C; Li, Hongliang; Velarde-Miranda, Carolina et al. (2014) Autoimmune mechanisms activating the angiotensin AT1 receptor in 'primary' aldosteronism. J Clin Endocrinol Metab 99:1790-7
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Gomez-Sanchez, Celso E; Oki, Kenji (2014) Minireview: potassium channels and aldosterone dysregulation: is primary aldosteronism a potassium channelopathy? Endocrinology 155:47-55
Chen, Jian; Gomez-Sanchez, Celso E; Penman, Alan et al. (2014) Expression of mineralocorticoid and glucocorticoid receptors in preautonomic neurons of the rat paraventricular nucleus. Am J Physiol Regul Integr Comp Physiol 306:R328-40
Gomez-Sanchez, Elise P (2014) Brain mineralocorticoid receptors in cognition and cardiovascular homeostasis. Steroids 91:20-31
Kuppusamy, Maniselvan; Caroccia, Brasilina; Stindl, Julia et al. (2014) A novel KCNJ5-insT149 somatic mutation close to, but outside, the selectivity filter causes resistant hypertension by loss of selectivity for potassium. J Clin Endocrinol Metab 99:E1765-73
Velarde-Miranda, Carolina; Gomez-Sanchez, Elise P; Gomez-Sanchez, Celso E (2013) Regulation of aldosterone biosynthesis by the Kir3.4 (KCNJ5) potassium channel. Clin Exp Pharmacol Physiol 40:895-901

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