The role of TASK1 in aldosterone production and its expression in normal adrenal and aldosterone-producing adenomas

摘要

Objectives Aldosterone production in the adrenal glomerulosa is mainly regulated by angiotensin II and K~+. Adrenal glomerulosa cells are uniquely sensitive to extracellular K~+. Genetic deletion of subunits of K~+-selective leak-channels (KCNK), TASK1 and/or TASK3, in mice generates animals with hyperaldosteronism and histological changes in the adrenal cortex. Herein, we studied the expression of TASK 1 in human adrenocortical cells, as well as its role in aldosterone production in H295R cells. Design TASK1 expression was investigated by comparative microarray analysis of aldosterone-producing adenomas (APA) and normal adrenals (NAs). The effects of TASK1 knockdown by siRNA transfection were investigated in H295R cells. Fluo-4 fluorescent measurements of intracellular Ca~(2 +) and pharmacological inhibition of Ca~(2 +) -dependent calmodulin kinases (CaMK) were performed to better define the effects of TASK 1 on Ca~(2 +) signalling pathways.Results Microarray analysis of APA and NA showed similar expression of TASK1 between these two groups. However, in APA, NA and H295R cells the expression of TASK1 was predominant when compared with other KCNK family members. Knockdown of TASK1 (with siRNA) induced the expression of steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2), and also stimulated pregnenolone and aldosterone production. Cells transfected with siTASKl had increased intracellular Ca~(2 +) , leading to activation of CaMK and increased expression of CYP11B2.