Lower expression of the Twik-related acid-sensitive K(+) channel 2 (TASK-2) gene is a hallmark of aldosterone producing adenoma causing human primary aldosteronism

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Item Type:	Article
Title:	Lower expression of the Twik-related acid-sensitive K(+) channel 2 (TASK-2) gene is a hallmark of aldosterone producing adenoma causing human primary aldosteronism
Creators Name:	Lenzini, L., Caroccia, B., Campos, A.G., Fassina, A., Belloni, A.S., Seccia, T.M., Kuppusamy, M., Ferraro, S., Skander, G., Bader, M., Rainey, W.E. and Rossi, G.P.
Abstract:	Context: The molecular mechanisms of primary aldosteronism, a common cause of human hypertension, are unknown, but alterations of K(+) channels can play a key role. Objective: To investigate: i) the expression of the Twik-related Acid-Sensitive K(+) channels (TASK) in Aldosterone Producing Adenomas (APAs); ii) the role of TASK-2 in aldosterone synthesis; iii) the determinants of TASK-2 blunted expression in APA. Design: We analyzed the transcriptome and the microRNA profiles of 32 consecutive APA and investigated the protein expression and localization of TASK-2 in APA and adrenocortical cell lines (H295R and HAC15) using immunoblotting and confocal microscopy. The functional effect of TASK-2 blunted activity caused by a dominant negative mutation on steroidogenic enzymes and aldosterone production was also assessed. TASK-2 regulation by selected microRNA was studied by a luciferase assay. Results: TASK-2 was consistently less expressed at the transcript and protein level in APAs than in the normal human adrenal cortex. H295R cells transfection with a TASK-2 dominant negative mutant construct significantly increased the aldosterone production by 153% and the gene expression of Aldosterone synthase (CYP11B2, gene expression fold change 3.1 vs control, p<0.05) and of the Steroidogenic acute regulatory protein (STAR) (gene expression fold change 1.8 vs control, p <0.05). Two microRNAs - hsa-miR-23 and hsa-miR-34- were found to decrease TASK-2 expression by binding to the 3' UTR of the TASK-2 gene. Conclusions: The TASK-2 channel lower expression represents a hallmark of APA and is associated to a higher expression of hsa-miR-23 and hsa-miR-34. The ensuing blunted TASK-2 activity increased the production of aldosterone in vitro and the expression of STAR and CYP11B2. Hence, the lower expression of TASK-2 channel in APA cells can explain high aldosterone secretion in human primary aldosteronism in spite of the suppression of angiotensin II, the hypertension and the hypokalemia.
Keywords:	Adenoma, Adrenal Cortex Neoplasms, Aldosterone, Cultured Cells, Down-Regulation, Gene Expression Profiling, Neoplastic Gene Expression Regulation, HEK293 Cells, Hyperaldosteronism, Microarray Analysis, Paraneoplastic Endocrine Syndromes, Tandem Pore Domain Potassium Channels
Source:	Journal of Clinical Endocrinology and Metabolism
ISSN:	0021-972X
Publisher:	Endocrine Society
Volume:	99
Number:	4
Page Range:	E674-E682
Date:	April 2014
Official Publication:	https://doi.org/10.1210/jc.2013-2900
PubMed:	View item in PubMed

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