Paracrine Regulation of Aldosterone Secretion in Physiological and Pathophysiological Conditions

Aldosterone secretion by the zona glomerulosa of the adrenal cortex is controlled by circulating factors including the renin angiotensin system (RAS) and potassium. Mineralocorticoid production is also regulated through an autocrine/paracrine mechanism by a wide variety of bioactive signals released in the vicinity of adrenocortical cells by chromaffin cells, nerve endings, cells of the immune system, endothelial cells and adipocytes. These regulatory factors include conventional neurotransmitters and neuropeptides. Their physiological role in the control of aldosterone secretion is not fully understood, but it is likely that they participate in the RAS-independent regulation of zona glomerulosa cells. Interestingly, recent observations indicate that autocrine/paracrine processes are involved in the pathophysiology of primary aldosteronism. The intraadrenal regulatory systems observed in aldosterone-producing adenomas (APA), although globally similar to those occurring in the normal adrenal gland, harbor alterations at different levels, which tend to strengthen the potency of paracrine signals to activate aldosterone secretion. Enhancement of paracrine stimulatory tone may participate to APA expansion and aldosterone hypersecretion together with somatic mutations of driver genes which activate the calcium signaling pathway and subsequently aldosterone synthase expression. Intraadrenal regulatory mechanisms represent thus promising pharmacological targets for the treatment of primary aldosteronism.