Severe Hyperaldosteronism in Neonatal Task3 Potassium Channel Knockout Mice Is Associated With Activation of the Intraadrenal Renin-Angiotensin System

Abstract

Task3 K(+) channels are highly expressed in the adrenal cortex and contribute to the angiotensin II and K(+) sensitivity of aldosterone-producing glomerulosa cells. Adult Task3(-/-) mice display a partially autonomous aldosterone secretion, subclinical hyperaldosteronism, and salt-sensitive hypertension. Here, we investigated the age dependence of the adrenal phenotype of Task3(-/-) mice. Compared with adults, newborn Task3(-/-) mice displayed a severe adrenal phenotype with strongly increased plasma levels of aldosterone, corticosterone, and progesterone. This adrenocortical dysfunction was accompanied by a modified gene expression profile. The most strongly up-regulated gene was the protease renin. Real-time PCR corroborated the strong increase in adrenal renin expression, and immunofluorescence revealed renin-expressing cells in the zona fasciculata. Together with additional factors, activation of the local adrenal renin system is probably causative for the severely disturbed steroid hormone secretion of neonatal Task3(-/-) mice. The changes in gene expression patterns of neonatal Task3(-/-) mice could also be relevant for other forms of hyperaldosteronism.

Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

“…Markedly increased intraadrenal expression of renin has also been observed in Task 3 potassium channel knockout mice and may at least partly explain the severe hyperaldosteronism associated with this model (34).…”

An update on novel mechanisms of primary aldosteronism

“…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).…”

Recovery of Current through Mutated TASK3 Potassium Channels Underlying Birk Barel Syndrome

“…TASK3 channels also play an important role in the migration of cortical pyramidal neurons during development (Bando et al, 2012), and TASK3 knockout mice show abnormalities in certain cognitive functions (Linden et al, 2007). TASK3 channels are proposed to play a role in various pathologic conditions such as epilepsy (Kananura et al, 2002), cancer Pei et al, 2003), ischemia (Ehling et al, 2010), idiopathic hyperaldosteronism, particularly in neonates (Davies et al, 2008;Bandulik et al, 2013), and low renin essential hypertension (Guagliardo et al, 2012;Penton et al, 2012).…”