Potassium channels related to primary aldosteronism: Expression similarities and differences between human and rat adrenals

Abstract

Three potassium channels have been associated with primary aldosteronism (PA) in rodents and humans: KCNK3 (TASK-1), KCNK9 (TASK-3), and KCNJ5 (Kir3.4). Mice with deficiency in Kcnk3 and Kcnk9 have elevated aldosterone production and blood pressure. In humans, adrenal tumors with somatic mutations in KCNJ5 cause PA. However, there are very few reports on the expression patterns of these genes in humans versus rodents. Herein, we compared human and rat mRNA expression (by quantitative real-time polymerase chain reaction (qPCR) and protein levels (by immunohistochemistry) across three tissues (adrenal, brain, heart) and two laser-captured adrenal zones (zona glomerulosa, zona fasciculata). Our findings show that expression patterns of KCNK3, KCNK9, and KCNJ5 are inconsistent between rats and humans across both tissues and adrenal zones. Thus, species variation in the expression of PA-related potassium channels indicates an evolutionary divergence in their role in regulating adrenal aldosterone production.

Functional TASK-3–Like Channels in Mitochondria of Aldosterone-Producing Zona Glomerulosa Cells

“…We found ample representation of the TASK-3 amplicon in H295R cDNA (Figure 5A). Relative gene expression was ∼240× more than that in HEK293T cells but ∼100× less than that in native mouse ZG tissue (Figure 5B), consistent with the quantitative disparity in levels of TASK-3 expression previously report in mouse and human adrenals 26 .…”

“…We note that in the normal human adrenal, there is a large difference in TASK-3 expression detected between adrenal layers; TASK-3 mRNA is found in the human ZG but at 100-fold lower levels than in the ZM 26 . We also find low levels of TASK-3 mRNA in H295R cells (∼100-fold less abundant than in rodent ZG).…”

“…Genetic variations in the human TASK-1 gene ( KCNK3 ) 21-23 are associated with measures of hypertension (rs1275988, rs13394970) and elevated plasma aldosterone (rs2586886), and KCNK3 mRNA is abundantly expressed in mouse and human adrenal cortex 24 . By contrast, the KCNK9 gene product, TASK-3, is principally expressed in the rodent adrenal cortex 25 , although low levels of message are detected in the human adrenal cortex 26 . The function of TASK-3 in adrenal cortical cells remains unknown.…”

Transcriptome Pathway Analysis of Pathological and Physiological Aldosterone-Producing Human Tissues

“…In agreement, little overlap was found between the most upregulated genes in ZG from the rodent study 16,40 and our human study (only 3 of the top 50: RGS4 , ATP10A , and PDE2A ), 17 and similarly different potassium channels were found to dominate the ZG K + currents in the 2 species. 43 In addition, we speculate that some of the species variation could be a result of human’s chronic exposure to salt. We hypothesize, in chronic salt environment, that the ZG cells in human adrenals undergo apoptosis when not producing aldosterone.…”

Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma

“…Even though spironolactone, a mineralocorticoid receptor antagonist, is available for the medical treatment of patients with APAs who elect not to undergo surgery, its use is associated with marked side effects, including gynecomastia, which often lim- KCNJ5 channels are not expressed in rodent zona glomerulosa (44), and a mouse model of KCNJ5…”