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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

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. and Caroccia, B. and Campos, A.G. and Fassina, A. and Belloni, A.S. and Seccia, T.M. and Kuppusamy, M. and Ferraro, S. and Skander, G. and Bader, M. and 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
Publisher:Endocrine Society
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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