ALDOSTERONE-PRODUCING ADENOMA CAUSING HUMAN PRIMARY ALDOSTERONISM ARE CHARACTERISED BY UNDER- EXPRESSION OF THE TWIK-RELATED ACID-SENSITIVE K+ CHANNEL 2 (TASK-2) GENE: PP.21.321

Abstract

Background: Primary aldosteronism is a common cause of arterial hypertension, but its underlying molecular mechanisms are unknown. However, it is well known that K+ is a key regulator of aldosterone secretion, which interacts with physiological secretagogues of aldosterone as angiotensin II (Ang II) and endothelin-1. Genetic manipulation of a widely distributed channels class, which generate background or “leak” potassium (K+) currents, the Twik-related Acid-Sensitive K channel 1 (TASK-1) and 3 (TASK-3), generated a phenotype that mimics human primary aldosteronism. Objective: To measure the expression of the TASK family in a series of aldosterone producing adenoma (APA). Methods: Whole transcriptome of 24 APA was compared to that of a normal adrenocortical tissue pool (n = 10) by oligomicroarray technique. Data were validated by quantitative real time RT PCR. Immunohistochemistry was used to investigate TASKs protein expression by adrenocortical tissues. Results and Conclusions: The most expressed TASK channel gene in both the normal ZG and in APAs was TASK-1, followed by TASK-2 while the expression of TASK-3 was scant. With a whole transcriptome analysis followed by confirmation with quantitative real time RT-PCR we found a consistent and marked under expression of TASK-2 channel in all studied APA (n = 24), while TASK-1 and TASK-3 were heterogeneously expressed, as compared to the normal adrenal cortex. Immunohistochemistry was used to confirm the expression of the 3 TASK K+ channels in the adrenal cortex at the protein level and quantitative immnunoblotting will be used to confirm the differences detected at the transcript level. The underexpression of TASK-2 channels in APA suggests blunted leak” K+ currents, with ensuing lowering of the membrane potential and thereby increased likelihood of opening of the voltage-gated T-type calcium channels. The latter is known to render the adrenocortical zona glomerulosa cells more sensitive to aldosterone secretagogues. Hence, our ex vivo findings, while pointing to TASK-2 channels under-expression as an important mechanism of primary aldosteronism, mandates further studies to ascertain the molecular mechanisms by which this underexpression develops.