Task3 Potassium Channel Gene Invalidation Causes Low Renin and Salt-Sensitive Arterial Hypertension

Abstract

Task1 and Task3 potassium channels (Task: tandem of P domains in a weak inward rectifying K ϩ channel-related acid-sensitive K ϩ channel) are believed to control the membrane voltage of aldosterone-producing adrenal glomerulosa cells. This study aimed at understanding the role of Task3 for the control of aldosterone secretion. The adrenal phenotype of Task3 Ϫ/Ϫ mice was investigated using electrophysiology, adrenal slices, and blood pressure measurements. Primary adrenocortical cells of Task3 Ϫ/Ϫ mice were strongly depolarized compared with wild-type (Ϫ52 vs.Ϫ79 mV), and in fresh adrenal slices Ca 2ϩ signaling of Task3 Ϫ/Ϫ glomerulosa cells was abnormal.In living Task3 Ϫ/Ϫ mice, the regulation of aldosterone secretion showed specific deficits: Under low Na ϩ and high K ϩ diets, protocols known to increase aldosterone, and under standard diet, Task3 inactivation was compensated and aldosterone was normal. However, high Na ϩ and low K ϩ diets, two protocols known to lower aldosterone, failed to lower aldosterone in Task3 Ϫ/Ϫ mice. The physiological regulation of aldosterone was disturbed: aldosterone-renin ratio, an indicator of autonomous aldosterone secretion, was 3-fold elevated at standard and high Na ϩ diets. Isolated adrenal glands of H igh blood pressure is one of the major cardiovascular risk factors (1). The pathogenesis of arterial hypertension, however, is very complex and encompasses environmental, genetic, vascular, and endocrine factors. Among the latter, inappropriately high aldosterone secretion is a common cause of salt and water retention resulting in hypertension. Recently, data from human genetics (2-4) pointed to a critical role of K ϩ channel defects as a cause of hyperaldosteronism.In adrenal glomerulosa cells, depolarization is considered to be the first step of a chain of events leading to aldosterone secretion (5). Glomerulosa cells have a very high K ϩ conductance leading to a hyperpolarized membrane potential close to the K ϩ equilibrium potential.

An update on novel mechanisms of primary aldosteronism

“…Among them, the most expressed are KCNK3 and KCNK5, encoding respectively TASK1 and TASK2. In contrast to animal models, however (Heitzmann et al 2008, Bandulik et al 2010, Penton et al 2012, to date no mutation in KCNK3 has been reported in APA. Similarly, the low expression of KCNK9, coding for TASK3, in human adrenal cortex is not in favor of a major role of this channel in the development of APA and no somatic mutations have been reported.…”

“…Deletions of the KCNK3 and KCNK9 genes coding for the two-pore domain potassium channels task1 and task3 lead to the development of different forms of hyperaldosteronism or low renin hypertension (Davies et al 2008, Heitzmann et al 2008, Guagliardo et al 2012b, Penton et al 2012. Genetic invalidation of task1 leads to adrenocortical cell depolarization and ectopic expression of CYP11B2 in ZF in female mice only, and to a glucocorticoid-remediable form of hyperaldosteronism resembling FH1 (Heitzmann et al 2008).…”

“…Genetic invalidation of task1 leads to adrenocortical cell depolarization and ectopic expression of CYP11B2 in ZF in female mice only, and to a glucocorticoid-remediable form of hyperaldosteronism resembling FH1 (Heitzmann et al 2008). Deletion of task3 in mice results in hyperaldosteronism in young animals and low renin hypertension in adults (Penton et al 2012, Bandulik et al 2013. Task1 and task3 double knock-out mice display a phenotype reminiscent of idiopathic primary hyperaldosteronism due to BAH with elevated levels of aldosterone and low circulating renin, and failure to suppress aldosterone production by dietary salt ingestion (Davies et al 2008).…”

Genetics in endocrinology: Genetics of mineralocorticoid excess: an update for clinicians

“…Finally, mice lacking TASK3 channels only display a mild hyperaldosteronism that is associated with low renin levels and an increased ARR. These animals display partially autonomous aldosterone production, which is not suppressed by high-sodium or low-potassium diets (49). It is likely that the constitutively depolarized state of glomerulosa cells in TASK3 K/K animals leads to partially autonomous aldosterone production, which is counterbalanced by a decreased activity of the renin-angiotensin axis.…”

“…As a consequence, the cell membrane potential closely follows the equilibrium potential of K C over a large range of extracellular K C concentrations. Among others, the physiological role of TASK channels has recently been highlighted by studies in various animal models in which genetic ablation of the channels results in a range of phenotypes with abnormal aldosterone production ( (47,48,49), see below). The concentration gradient of K C between the intracellular and extracellular spaces, which is required for the establishment of the membrane potential, is generated by the activity of the Na C , K C -ATPase, which transports two K C ions into and three Na C ions out of the cell.…”