Primary Aldosteronism with Aldosterone-Producing Adenoma Consisting of Pure Zona Glomerulosa-Type Cells in a Pregnant Woman

Abstract

C a 2+ is a critical signal for adrenal and gonadal steroid synthesis 1 acting within 2 cellular compartments; Ca 2+ is generated in the cytosol 2,3 and transferred to the mitochondria 4-7 where it activates matrix dehydrogenases to generate reducing equivalents (NAD(P)H) that are essential cofactors for steroid hydroxylation. 8 In aldosterone-producing zona glomerulosa (ZG) cells of the adrenal cortex, the dominant pathway for extra-cellular Ca 2+ entry into the cytoplasmic compartment is plasma membrane voltage-gated Ca 2+ channels, 9 whereas the principal pathway for mitochondrial Ca 2+ uptake is via the mitochon-drial uniporter, a Ca 2+-selective channel. 10 Membrane voltage across each of these compartments regulates Ca 2+ transport and thus the rate of steroid production. Because other ion channels resident in each membrane (plasma and mitochondrial) can change membrane voltage, they too are capable of altering Ca 2+ uptake by mitochondria. 11 Accordingly, it is not surprising that genetic variation in genes encoding ion channels and transporters is now considered central to the pathophysiology of 1 common subtype of primary hyperaldosteronism, unilateral aldosterone-producing adenoma. 12 In aldosterone-producing adenoma, aldosterone synthesis is not strictly controlled by the renin-angiotensin II system and thus is characterized by a large increase in the aldosterone/renin ratio. 13 Yet, the cause of other common endocrine hypertensive disorders in which aldosterone production is inappropriate for the level of renin, such as bilateral adrenal hyperplasia and low renin essential hypertension, 14,15 still remains poorly understood. Our laboratory and that of Barhanin et al have generated mouse models of aldosterone overproduction evoked by deletion of leak potassium channels that generate background currents to establish a negative resting cell membrane voltage. 16-20 The combined deletion of TASK-1 and TASK-3 channels (tandem pore domain acid-sensitive K + channels) leads to excessive aldosterone overproduction and low renin in mice. By contrast, deletion of TASK-3 alone evokes mild hyperal-dosteronism and low renin, 19 whereas that of TASK-1 elicits mild hyperaldosteronism without an accompanying suppression of renin. 21 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. We previously reported that global deletion of TASK-3 in mice produces a mild hyperaldosteronism even though the cell Abstract-Ca 2+ drives aldosterone synthesis in the cytosolic and mitochondrial compartments of the adrenal zona glomerulosa cell. Membrane potential across each of these compartments regu...

Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

“…During pregnancy, hypertension and symptoms may improve (49,210,424). This is thought to be due to the anti-mineralocorticoid effects of high circulating levels of placental progesterone, which antagonize aldosterone action at the MR. On the other hand, several case reports exist of PA presenting during pregnancy (17,127,466,518). In one of these (518), APAs from both affected patients harbored somatic mutations in CTNNB1, encoding ␤-catenin in the Wnt celldifferentiation pathway (which may in part explain tumor development).…”

Sporadic solitary aldosterone- and cortisol-co-secreting adenomas: endocrine, histological and genetic findings in a subtype of primary aldosteronism

“…52 Therefore, immunohistochemistry for 17a-hydroxylase expression will most likely not result in specific detection of an A/CPA subtype of PA, as suggested by others. 20 Instead, we suggest that laboratory criteria be applied for diagnosing A/CPA.…”

Estrogen Signaling in the Adrenal Cortex

“…92,108,109 In 2009, a pregnant woman with aldosterone-producing adenoma (APA) was described to have a predominant expression of ERβ, suggesting a similar expression pattern of ERs in these tumors and in the normal adrenal gland. 110 At variance, by systematically examining both GPER-1 and ERα36 expressions in APA, we found markedly different ER mRNA levels between tumors and the normal gland: the GPER-1 prevailed in the former, ERβ in the latter tissue, whereas both ERα and ERα36 were scarcely expressed ( Figure S2). 69 CD56 + aldosterone-producing cells isolated from APAs also exhibited GPER-1 higher expression than ERβ and ERα, supporting the view that GPER-1 predominates in the aldosterone-producing cells.…”