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

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