Regulation of aldosterone production by ion channels: From basal secretion to primary aldosteronism

Yang, Tingting; He, Min; Hu, Changlong

doi:10.1016/j.bbadis.2017.12.034

Cited by 17 publications

(12 citation statements)

References 136 publications

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“…Mutations in several genes encoding ion channels of ZG cells cause human PA 10,11,50 . Progress in understanding the underlying pathological mechanisms has been hampered by the absence of mouse models that faithfully replicate the human disease 51 .…”

Section: Discussionmentioning

confidence: 99%

Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism

et al. 2019

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Human primary aldosteronism (PA) can be caused by mutations in several ion channel genes but mouse models replicating this condition are lacking. We now show that almost all known PA-associated CLCN2 mutations markedly increase ClC-2 chloride currents and generate knock-in mice expressing a constitutively open ClC-2 Cl− channel as mouse model for PA. The Clcn2op allele strongly increases the chloride conductance of zona glomerulosa cells, provoking a strong depolarization and increasing cytoplasmic Ca2+ concentration. Clcn2op mice display typical features of human PA, including high serum aldosterone in the presence of low renin activity, marked hypertension and hypokalemia. These symptoms are more pronounced in homozygous Clcn2op/op than in heterozygous Clcn2+/op mice. This difference is attributed to the unexpected finding that only ~50 % of Clcn2+/op zona glomerulosa cells are depolarized. By reproducing essential features of human PA, Clcn2op mice are a valuable model to study the pathological mechanisms underlying this disease.

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Section: Discussionmentioning

confidence: 99%

Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism

et al. 2019

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“…However, previous studies indicate that the activity of the T-type, but not that of the L-type channel, correlates with aldosterone secretion in dispersed preparations of animal ZG cells and human adrenocortical cell lines (Barrett et al 1995, Rossier et al 1996b, Imagawa et al 2006, Akizuki et al 2008. Thus, surprisingly recent clinical studies have found more than 25 different somatic Ca V 1.3 L-type calcium channels mutations in patients with PA (Yang et al 2018), suggesting that in humans L-type calcium channels may also play an equally important role in controlling aldosterone production.…”

Section: Introductionmentioning

confidence: 99%

“…Idiopathic hyperaldosteronism and aldosterone-producing adenoma are the two most common subtypes of PA (Funder et al 2008, Monticone et al 2017. Notably, somatic mutations of potassium and calcium channels have been found in more than half of aldosterone-producing adenomas (Yang et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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L- and T-type calcium channels control aldosterone production from human adrenals

Yang

Zhang

et al. 2020

Journal of Endocrinology

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Journal of Endocrinology244:1 237-247 T Yang, M He et al. Ca 2+ channels control aldosterone secretion AbstractAldosterone, which plays a key role in the regulation of blood pressure, is produced by zona glomerulosa (ZG) cells of the adrenal cortex. Exaggerated overproduction of aldosterone from ZG cells causes primary hyperaldosteronism. In ZG cells, calcium entry through voltage-gated calcium channels plays a central role in the regulation of aldosterone secretion. Previous studies in animal adrenals and human adrenal adrenocortical cell lines suggest that the T-type but not the L-type calcium channel activity drives aldosterone production. However, recent clinical studies show that somatic mutations in L-type calcium channels are the second most prevalent cause of aldosterone-producing adenoma. Our objective was to define the roles of T and L-type calcium channels in regulating aldosterone secretion from human adrenals. We find that human adrenal ZG cells mainly express T-type Ca V 3.2/3.3 and L-type Ca V 1.2/1.3 calcium channels. TTA-P2, a specific inhibitor of T-type calcium channel subtypes, reduced basal aldosterone secretion from acutely prepared slices of human adrenals. Surprisingly, nifedipine, the prototypic inhibitor of L-type calcium channels, also decreased basal aldosterone secretion, suggesting that L-type calcium channels are active under basal conditions. In addition, TTA-P2 or nifedipine also inhibited aldosterone secretion stimulated by angiotensin II-or elevations in extracellular K + . Remarkably, blockade of either L-or T-type calcium channels inhibits basal and stimulated aldosterone production to a similar extent. Low concentrations of TTA-P2 and nifedipine showed additive inhibitory effect on aldosterone secretion. We conclude that T-and L-type calcium channels play equally important roles in controlling aldosterone production from human adrenals.caused by autonomous overproduction of aldosterone, is the most common form of secondary endocrine hypertension (Stowasser 2001). Approximately 10% of hypertensive patients have PA (Rossi et al. 2006,

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“…Elevated ECF potassium promotes membrane depolarization in the adrenal zona glomerulosa, triggering voltage-dependent mechanisms that ultimately induce aldosterone release (Lotshaw, 2001;Yang et al, 2016Yang et al, , 2018. Aldosterone secretion requires a change in potassium current across the cell membrane (Yang et al, 2018), increasing roughly 100-fold per 1 mM rise in extracellular potassium (Lotshaw, 2001). In human patients, the importance of potassium for aldosterone release was solidified by the discovery that a frequent cause of primary hyperaldosteronism is a somatic KCNJ5 mutation that disrupts the potassium-selectivity of the Kir3.4 channel, allowing sodium entry through this channel to inappropriately depolarize aldosterone-secreting cells (Choi et al, 2011).…”

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confidence: 99%

Despite increasing aldosterone, elevated potassium is not necessary for activating aldosterone‐sensitive HSD2 neurons or sodium appetite

et al. 2021

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Sodium appetite is a complex, motivated behavioral state. It requires low-sodium status detection and a coordinated drive to seek and ingest salty foods. Interestingly, this elaborate behavior can be elicited by administering a singular hormone, aldosterone (Formenti et al., 2013; Gasparini et al., 2018; Geerling & Loewy, 2008). Aldosterone is a mineralocorticoid produced in the zona glomerulosa of the adrenal cortex. It affects cells that express the mineralocorticoid receptor (MR) by translocating this receptor into the cell nucleus to promote genomic activity (Robertson et al., 1993). Aldosterone-sensitive cells also require the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (HSD2), which protects the MR from glucocorticoids, leaving it more accessible to aldosterone (Funder et al., 1988; Naray-Fejes-Toth et al.,

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Regulation of aldosterone production by ion channels: From basal secretion to primary aldosteronism

Cited by 17 publications

References 136 publications

Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism

Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism

L- and T-type calcium channels control aldosterone production from human adrenals

Despite increasing aldosterone, elevated potassium is not necessary for activating aldosterone‐sensitive HSD2 neurons or sodium appetite

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