Role of ACTH and Other Hormones in the Regulation of Aldosterone Production in Primary Aldosteronism

Abstract

The major physiological regulators of aldosterone production from the adrenal zona glomerulosa are potassium and angiotensin II; other acute regulators include adrenocorticotropic hormone (ACTH) and serotonin. Their interactions with G-protein coupled hormone receptors activate cAMP/PKA pathway thereby regulating intracellular calcium flux and CYP11B2 transcription, which is the specific steroidogenic enzyme of aldosterone synthesis. In primary aldosteronism (PA), the increased production of aldosterone and resultant relative hypervolemia inhibits the renin and angiotensin system; aldosterone secretion is mostly independent from the suppressed renin-angiotensin system, but is not autonomous, as it is regulated by a diversity of other ligands of various eutopic or ectopic receptors, in addition to activation of calcium flux resulting from mutations of various ion channels. Among the abnormalities in various hormone receptors, an overexpression of the melanocortin type 2 receptor (MC2R) could be responsible for aldosterone hypersecretion in aldosteronomas. An exaggerated increase in plasma aldosterone concentration (PAC) is found in patients with PA secondary either to unilateral aldosteronomas or bilateral adrenal hyperplasia (BAH) following acute ACTH administration compared to normal individuals. A diurnal increase in PAC in early morning and its suppression by dexamethasone confirms the increased role of endogenous ACTH as an important aldosterone secretagogue in PA. Screening using a combination of dexamethasone and fludrocortisone test reveals a higher prevalence of PA in hypertensive populations compared to the aldosterone to renin ratio. The variable level of MC2R overexpression in each aldosteronomas or in the adjacent zona glomerulosa hyperplasia may explain the inconsistent results of adrenal vein sampling between basal levels and post ACTH administration in the determination of source of aldosterone excess. In the rare cases of glucocorticoid remediable aldosteronism, a chimeric CYP11B2 becomes regulated by ACTH activating its chimeric CYP11B1 promoter of aldosterone synthase in bilateral adrenal fasciculate-like hyperplasia. This review will focus on the role of ACTH on excess aldosterone secretion in PA with particular focus on the aberrant expression of MC2R in comparison with other aberrant ligands and their GPCRs in this frequent pathology.

Keywords: ACTH; aberrant G-protein coupled receptors; aldosterone regulation; melanocortin type 2 receptor; primary aldosteronism.

Figure 1

Mechanisms responsible for aldosterone synthesis in zona glomerulosa cells under normal physiological conditions and excess production in primary aldosteronism. The strongly negative resting membrane potential of zona glomerulosa (ZG) cells under resting physiological conditions is maintained by the concentration gradient of K⁺ between the intracellular and extracellular space, which is generated by the activity of the Na⁺, K⁺-ATPase. Angiotensin II and increased K⁺ lead to cell membrane depolarization, which opens voltage-dependent Ca²⁺ channels. Furthermore, Angiostensin II acts through the Angiotensin II type 1 receptor (AT1R) inducing Ca²⁺ release from the endoplasmic reticulum. Consequently, the increase in intracellular Ca²⁺ concentration activates the calcium signaling pathway, which triggers activation of CYP11B2 transcription. The role for ACTH in the regulation of aldosterone secretion whether in normal physiology or in PA is in part determined by the level of expression of ACTH receptors (MC2R) in ZG cells. MC2R which is a GPCR coupled to the stimulatory Gsα subunit may induce an increase of intracellular cAMP concentration which activates protein kinase A thereby increasing CREB phosphorylation and CYP11B2 transcription. Aberrant expression of other GPCR may also be responsible for aldosterone excess despite a suppressed renin angiotensin system: eutopic GPCR include those for serotonin (5-HT₄R); ectopic GPCR include those for glucose-dependent insulinotropic peptide (GIPR), luteinizing hormone/human chorionic gonadotropin (LH–hCG R), β-adrenergic receptors (β-AR), vasopressin (V1-AVPR) glucagon (glucagon receptor), TRH (TRH R), and Endothelin-1 ET_A and ET_B receptors. Other mechanisms implicated in PA involve somatic and germline mutations in ion channels genes regulating intracellular ionic homeostasis and cell membrane potentials: increase intracellular Na⁺ concentrations and cell membrane depolarization result from KCNJ5 gain-of-function mutations affecting GIRK4 and ATP1A1 mutations of the Na⁺, K⁺-ATPase. Direct increase of intracellular Ca²⁺ concentrations could also result from mutations in ATP2B3 encoding for the plasma membrane Ca²⁺-ATPase, mutations in CACNA1D affecting the Cav1.3 subunit of the L-type voltage-gated calcium channel or CACNA1H affecting the Cav3.2 subunit of the voltage-gated calcium channel. Finally dysregulation in cellular proliferation/apoptosis accelerating adenoma formation could be due either to activation of the Wnt/β-catenin pathway or to gene mutations such as ARMC5 although the mechanism of the latter mutation is not fully elucidated.