TASK channel deletion in mice causes primary hyperaldosteronism

Abstract

When inappropriate for salt status, the mineralocorticoid aldosterone induces cardiac and renal injury. Autonomous overproduction of aldosterone from the adrenal zona glomerulosa (ZG) is also the most frequent cause of secondary hypertension. Yet, the etiology of nontumorigenic primary hyperaldosteronism caused by bilateral idiopathic hyperaldosteronism remains unknown. Here, we show that genetic deletion of TWIK-related acid-sensitive K (TASK)-1 and TASK-3 channels removes an important background K current that results in a marked depolarization of ZG cell membrane potential. Although TASK channel deletion mice (TASK −/− ) adjust urinary Na excretion and aldosterone production to match Na intake, they produce more aldosterone than control mice across the range of Na intake. Overproduction of aldosterone is not the result of enhanced activity of the renin–angiotensin system because circulating renin concentrations remain either unchanged or lower than those of control mice at each level of Na intake. In addition, TASK −/− mice fail to suppress aldosterone production in response to dietary Na loading. Autonomous aldosterone production is also demonstrated by the failure of an angiotensin type 1 receptor blocker, candesartan, to normalize aldosterone production to control levels in TASK −/− mice. Thus, TASK −/− channel knockout mice exhibit the hallmarks of primary hyperaldosteronism. Our studies establish an animal model of nontumorigenic primary hyperaldosteronism and identify TASK channels as a possible therapeutic target for primary hyperaldosteronism.

Integrating Genetics and Genomics in Primary Aldosteronism

“…The mice showed low renin hyperaldosteronism partly responsive to sodium diet, with a phenotype reminiscent of patients with idiopathic primary hyperaldosteronism. 58 Although these models suggest that hypomorphic alleles of the KCNK3 and KCNK9 genes, coding for TASK1 and TASK3, respectively, may play a role in the development of PA in humans, sequencing of these genes in 22 patients with APA, 59 as well as in both germinal and somatic DNA from a large cohort of patients with PA in our laboratory, 60 has not led to the identification of causative mutations.…”

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

“…Mice with single deletions of the Task1 or Task3 gene as well as Task1/Task3 double knockout mice display partially autonomous aldosterone synthesis. These deletions also have a profound impact on adrenal zonation (Davies et al 2008, Heitzmann et al 2008. Indeed, deletion of Task1 changed adrenal zonation and expression of CYP11B2, which was absent in the outermost ZG but was expressed to a large extent in the ZF.…”

An Extracellular Ion Pathway Plays a Central Role in the Cooperative Gating of a K2P K+ Channel by Extracellular pH*

“…Examples are TASK subfamily K 2P channels TASK-1 (K 2P 3.1) and TASK-3 (K 2P 9.1), which are exquisitely sensitive to extracellular proton concentration (8 -11). TASK-3 is fundamental to various cellular functions including the modulation of sleep (12), aldosterone/renin secretion (13,14), and O 2 sensing (15), and its dysfunction has been linked to the Birk Barel mental retardation dysmorphism syndrome (16). TASK-3 is inactive (closed) at acid extracellular pH (pH o ) but activates (opens) as pH o is increased.…”