folder

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

Authors

  • L. Lenzini
  • B. Caroccia
  • A.G. Campos
  • A. Fassina
  • A.S. Belloni
  • T.M. Seccia
  • M. Kuppusamy
  • S. Ferraro
  • G. Skander
  • M. Bader
  • W.E. Rainey
  • G.P. Rossi

Journal

  • Journal of Clinical Endocrinology and Metabolism

Citation

  • J Clin Endocrinol Metab 99 (4): E674-E682

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.


DOI

doi:10.1210/jc.2013-2900