Of Mice and Man and the Regulation of Aldosterone Secretion

Abstract

See related article, pp 347–356 Aldosterone is the most important mineralocorticoid for electrolyte and fluid homeostasis in mammals, birds, and some members of other orders. Although critical for life, even subtle inappropriate increases in aldosterone contribute to the development of hypertension and cardiovascular damage. Primary aldosteronism (PA), the autonomous and excessive secretion of aldosterone, is the most common form of secondary hypertension and is associated with more pathological cardiovascular remodeling than essential hypertension of a similar duration and severity. Aldosterone-producing adenomas and idiopathic hyperaldosteronism are responsible for most PA. Despite the importance of PA in cardiovascular and renal disease, its pathogenesis is only partially clarified in aldosterone-producing adenomas and remains unknown in idiopathic hyperaldosteronism. A report in this issue by Yao et al1 provides crucial new information on the normal control of aldosterone synthesis that could elucidate mechanisms for its dysregulation in PA. They used elegant technology to demonstrate that TASK-3 K+ channels (tandem pore domain acid-sensitive K+ channels) locate in the mitochondria and interact with proteins of the electron transport chain of the mitochondrial inner membrane and regulate mitochondrial membrane potential and morphology. They also showed that TASK-3 channels interact with the P450 side-chain cleavage enzyme that catalyzes the first step in the synthesis of all steroids from cholesterol, as well as with CYP11B2, or aldosterone synthase, the last and unique enzyme in a series of enzymatic reactions within the mitochondria. Synthesis of aldosterone is regulated primarily by angiotensin II (Ang-II) and plasma potassium (K+), with lesser influence by adrenocorticotropic hormone and several paracrine factors2 at 2 points in its synthetic pathway. Within minutes after stimulation by Ang-II or K+, …