<i>DACH1</i>
            , a Zona Glomerulosa Selective Gene in the Human Adrenal, Activates Transforming Growth Factor-β Signaling and Suppresses Aldosterone Secretion

Zhou, Junhua; Shaikh, Lalarukh Haris; Neogi, Sudeshna Guha; McFarlane, Ian G.; Zhao, Wanfeng; Figg, Nichola; Brighton, Cheryl A.; Maniero, Carmela; Teo, Ada; Azizan, Elena

doi:10.1161/hyp.0000000000000025

Cited by 22 publications

(46 citation statements)

References 40 publications

(48 reference statements)

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“…We have noted aldosterone secretion and synthesis to change in opposite directions in previous published experiments 21 and infer that this points to regulatory influences downstream of transcription, for instance on cholesterol uptake into the inner mitochondrial membrane via the steroidogenic acute regulatory protein. Although in recent years the emphasis in pathways to aldosterone secretion has been via stimuli to CYP11B2 transcription, earlier literature showed that many effects, including postural changes and those of dopamine, occur within minutes-namely too fast for a transcriptional response.…”

Section: Discussionmentioning

confidence: 53%

“…NEFM was the fourth most upregulated gene in ZG. 21 Moreover, its expression was ≈4-fold higher in ZG-like versus ZF-like APAs. 22 Our previous functional studies of 2 of the ZG-specific genes, LGR5 and DACH1, showed that they inhibit aldosterone secretion and proliferation.…”

Section: Discussionmentioning

confidence: 96%

“…This surprising finding, together with their absence from upregulated genes in rodent ZG 26 and patchiness of aldosterone synthase in human adrenal, was interpreted as an adaptive mechanism to high-salt intake in Western diet. 20,21 NEFM encodes one of the subunits forming the neurofilament, the type IV intermediate filament of mature neurons, one of the most abundant proteins in the nervous system. Neurofilament subunits perform extracytoskeletal roles in the neuronal synapses as receptor-interacting proteins.…”

Section: Discussionmentioning

confidence: 99%

“…20,21 NEFM is also a biomarker for the wild-type, ZG-like subtype of APAs; compared with these, it was 4-fold downregulated in KCNJ5 mutant, ZF-like APAs. 22 We hypothesized that NEFM plays a role in regulating human ZG endocrine function through a similar relationship with D1R as described in the nervous system.…”

Section: August 2017mentioning

confidence: 99%

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NEFM (Neurofilament Medium) Polypeptide, a Marker for Zona Glomerulosa Cells in Human Adrenal, Inhibits D1R (Dopamine D1 Receptor)–Mediated Secretion of Aldosterone

et al. 2017

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A ldosterone-producing adenomas (APAs) are responsible for ≈5% of hypertension and are probably its most common curable cause. 1 The heterogeneity of these tumors has been highlighted by the landmark discovery of somatic mutations of KCNJ5, followed by others in ATP2B3, ATP1A1, CACNA1D, and CTNNB1. [2][3][4][5] The genotype and histological features delineate 2 overlapping APA subtypes: the common, large KCNJ5 mutant APAs histology is usually similar to cortisol-producing zona fasciculata (ZF) and smaller APAs with other mutations are mainly composed of zona glomerulosa (ZG)-like compact, lipid-depleted cells.The 2 subtypes present other phenotypic differences: for instance, elevated secretion from an APA of hybrid steroids 18-hydroxycortisol and 18-oxocortisol could be considered a fingerprint of KCNJ5 mutation.6 Further differences about the response to aldosterone secretagogues, such as angiotensin II or metoclopramide, have been previously reported. 7,8 Dopamine is one of the main regulators of aldosterone secretion. 9 The 5 known dopamine receptors belong to the G-protein-coupled receptor superfamily and are classified into 2 major subgroups (D1-like and D2-like) according to their structure and opposite action on cAMP production. Activation of the D1-like subfamily members (D1R and D5R) causes an increase of intracellular cAMP levels. The D2-like subfamily includes D2R, D3R, and D4R receptors; their transduction of signal causes a reduction of cAMP production. 10In human adrenal, most attention has been paid to the D2R subtype. This is expressed in normal ZG and mediates dopamine inhibition of aldosterone response to angiotensin II (but not to adrenocorticotropic hormone or potassium) 11,12 and tonic

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: August 2017mentioning

confidence: 99%

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NEFM (Neurofilament Medium) Polypeptide, a Marker for Zona Glomerulosa Cells in Human Adrenal, Inhibits D1R (Dopamine D1 Receptor)–Mediated Secretion of Aldosterone

et al. 2017

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“…46,47 DACH1 was found to be 10-fold more expressed in ZG than in ZF and APA cells; 48 its silencing in H295R cells increases aldosterone synthesis and over-expression decreases it. Stimulation of primary human adrenal cells with Angiotensin II to markedly increase CYP11B2, leading to 2.4-fold increase in aldosterone production, blunted DACH1 gene expression.…”

Section: Dach1: a Cyp11b2 Suppressormentioning

confidence: 93%

Review of Markers of Zona Glomerulosa and Aldosterone-Producing Adenoma Cells

et al. 2017

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Primary aldosteronism: molecular medicine meets public health

Azizan,

Drake,

Brown

2023

Nat Rev Nephrol

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Primary aldosteronism is the most common single cause of hypertension and is potentially curable when only one adrenal gland is the culprit. The importance of primary aldosteronism to public health derives from its high prevalence but huge under-diagnosis (estimated to be <1% of all affected individuals), despite the consequences of poor blood pressure control by conventional therapy and enhanced cardiovascular risk. This state of affairs is attributable to the fact that the tools used for diagnosis or treatment are still those that originated in the 1970–1990s. Conversely, molecular discoveries have transformed our understanding of adrenal physiology and pathology. Many molecules and processes associated with constant adrenocortical renewal and interzonal metamorphosis also feature in aldosterone-producing adenomas and aldosterone-producing micronodules. The adrenal gland has one of the most significant rates of non-silent somatic mutations, with frequent selection of those driving autonomous aldosterone production, and distinct clinical presentations and outcomes for most genotypes. The disappearance of aldosterone synthesis and cells from most of the adult human zona glomerulosa is the likely driver of the mutational success that causes aldosterone-producing adenomas, but insights into the pathways that lead to constitutive aldosterone production and cell survival may open up opportunities for novel therapies.

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DACH1 , a Zona Glomerulosa Selective Gene in the Human Adrenal, Activates Transforming Growth Factor-β Signaling and Suppresses Aldosterone Secretion

Abstract: Supplemental Digital Content is available in the text.

Cited by 22 publications

References 40 publications

NEFM (Neurofilament Medium) Polypeptide, a Marker for Zona Glomerulosa Cells in Human Adrenal, Inhibits D1R (Dopamine D1 Receptor)–Mediated Secretion of Aldosterone

NEFM (Neurofilament Medium) Polypeptide, a Marker for Zona Glomerulosa Cells in Human Adrenal, Inhibits D1R (Dopamine D1 Receptor)–Mediated Secretion of Aldosterone

Review of Markers of Zona Glomerulosa and Aldosterone-Producing Adenoma Cells

Primary aldosteronism: molecular medicine meets public health

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