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

Common somatic mutations in CACNAID and ATP1A1 may define a subgroup of smaller, zona glomerulosa (ZG)–like aldosterone-producing adenomas. We have therefore sought signature ZG genes, which may provide insight into the frequency and pathogenesis of ZG-like aldosterone-producing adenomas. Twenty-one...

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Autores principales: Zhou, Junhua, Shaikh, Lalarukh Haris, Neogi, Sudeshna G., McFarlane, Ian, Zhao, Wanfeng, Figg, Nichola, Brighton, Cheryl A., Maniero, Carmela, Teo, Ada E.D., Azizan, Elena A. B., Brown, Morris J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott, Williams & Wilkins 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387203/
https://www.ncbi.nlm.nih.gov/pubmed/25776071
http://dx.doi.org/10.1161/HYP.0000000000000025
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author Zhou, Junhua
Shaikh, Lalarukh Haris
Neogi, Sudeshna G.
McFarlane, Ian
Zhao, Wanfeng
Figg, Nichola
Brighton, Cheryl A.
Maniero, Carmela
Teo, Ada E.D.
Azizan, Elena A. B.
Brown, Morris J.
author_facet Zhou, Junhua
Shaikh, Lalarukh Haris
Neogi, Sudeshna G.
McFarlane, Ian
Zhao, Wanfeng
Figg, Nichola
Brighton, Cheryl A.
Maniero, Carmela
Teo, Ada E.D.
Azizan, Elena A. B.
Brown, Morris J.
author_sort Zhou, Junhua
collection PubMed
description Common somatic mutations in CACNAID and ATP1A1 may define a subgroup of smaller, zona glomerulosa (ZG)–like aldosterone-producing adenomas. We have therefore sought signature ZG genes, which may provide insight into the frequency and pathogenesis of ZG-like aldosterone-producing adenomas. Twenty-one pairs of zona fasciculata and ZG and 14 paired aldosterone-producing adenomas from 14 patients with Conn’s syndrome and 7 patients with pheochromocytoma were assayed by the Affymetrix Human Genome U133 Plus 2.0 Array. Validation by quantitative real-time polymerase chain reaction was performed on genes >10-fold upregulated in ZG (compared with zona fasciculata) and >10-fold upregulated in aldosterone-producing adenomas (compared with ZG). DACH1, a gene associated with tumor progression, was further analyzed. The role of DACH1 on steroidogenesis, transforming growth factor-β, and Wnt signaling activity was assessed in the human adrenocortical cell line, H295R. Immunohistochemistry confirmed selective expression of DACH1 in human ZG. Silencing of DACH1 in H295R cells increased CYP11B2 mRNA levels and aldosterone production, whereas overexpression of DACH1 decreased aldosterone production. Overexpression of DACH1 in H295R cells activated the transforming growth factor-β and canonical Wnt signaling pathways but inhibited the noncanonical Wnt signaling pathway. Stimulation of primary human adrenal cells with angiotensin II decreased DACH1 mRNA expression. Interestingly, there was little overlap between our top ZG genes and those in rodent ZG. In conclusion, (1) the transcriptome profile of human ZG differs from rodent ZG, (2) DACH1 inhibits aldosterone secretion in human adrenals, and (3) transforming growth factor-β signaling pathway is activated in DACH1 overexpressed cells and may mediate inhibition of aldosterone secretion in human adrenals.
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spelling pubmed-43872032015-04-10 DACH1, 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 G. McFarlane, Ian Zhao, Wanfeng Figg, Nichola Brighton, Cheryl A. Maniero, Carmela Teo, Ada E.D. Azizan, Elena A. B. Brown, Morris J. Hypertension Original Articles Common somatic mutations in CACNAID and ATP1A1 may define a subgroup of smaller, zona glomerulosa (ZG)–like aldosterone-producing adenomas. We have therefore sought signature ZG genes, which may provide insight into the frequency and pathogenesis of ZG-like aldosterone-producing adenomas. Twenty-one pairs of zona fasciculata and ZG and 14 paired aldosterone-producing adenomas from 14 patients with Conn’s syndrome and 7 patients with pheochromocytoma were assayed by the Affymetrix Human Genome U133 Plus 2.0 Array. Validation by quantitative real-time polymerase chain reaction was performed on genes >10-fold upregulated in ZG (compared with zona fasciculata) and >10-fold upregulated in aldosterone-producing adenomas (compared with ZG). DACH1, a gene associated with tumor progression, was further analyzed. The role of DACH1 on steroidogenesis, transforming growth factor-β, and Wnt signaling activity was assessed in the human adrenocortical cell line, H295R. Immunohistochemistry confirmed selective expression of DACH1 in human ZG. Silencing of DACH1 in H295R cells increased CYP11B2 mRNA levels and aldosterone production, whereas overexpression of DACH1 decreased aldosterone production. Overexpression of DACH1 in H295R cells activated the transforming growth factor-β and canonical Wnt signaling pathways but inhibited the noncanonical Wnt signaling pathway. Stimulation of primary human adrenal cells with angiotensin II decreased DACH1 mRNA expression. Interestingly, there was little overlap between our top ZG genes and those in rodent ZG. In conclusion, (1) the transcriptome profile of human ZG differs from rodent ZG, (2) DACH1 inhibits aldosterone secretion in human adrenals, and (3) transforming growth factor-β signaling pathway is activated in DACH1 overexpressed cells and may mediate inhibition of aldosterone secretion in human adrenals. Lippincott, Williams & Wilkins 2015-05 2015-04-08 /pmc/articles/PMC4387203/ /pubmed/25776071 http://dx.doi.org/10.1161/HYP.0000000000000025 Text en © 2015 The Authors. Hypertension is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/3.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
spellingShingle Original Articles
Zhou, Junhua
Shaikh, Lalarukh Haris
Neogi, Sudeshna G.
McFarlane, Ian
Zhao, Wanfeng
Figg, Nichola
Brighton, Cheryl A.
Maniero, Carmela
Teo, Ada E.D.
Azizan, Elena A. B.
Brown, Morris J.
DACH1, a Zona Glomerulosa Selective Gene in the Human Adrenal, Activates Transforming Growth Factor-β Signaling and Suppresses Aldosterone Secretion
title DACH1, a Zona Glomerulosa Selective Gene in the Human Adrenal, Activates Transforming Growth Factor-β Signaling and Suppresses Aldosterone Secretion
title_full DACH1, a Zona Glomerulosa Selective Gene in the Human Adrenal, Activates Transforming Growth Factor-β Signaling and Suppresses Aldosterone Secretion
title_fullStr DACH1, a Zona Glomerulosa Selective Gene in the Human Adrenal, Activates Transforming Growth Factor-β Signaling and Suppresses Aldosterone Secretion
title_full_unstemmed DACH1, a Zona Glomerulosa Selective Gene in the Human Adrenal, Activates Transforming Growth Factor-β Signaling and Suppresses Aldosterone Secretion
title_short DACH1, a Zona Glomerulosa Selective Gene in the Human Adrenal, Activates Transforming Growth Factor-β Signaling and Suppresses Aldosterone Secretion
title_sort dach1, a zona glomerulosa selective gene in the human adrenal, activates transforming growth factor-β signaling and suppresses aldosterone secretion
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387203/
https://www.ncbi.nlm.nih.gov/pubmed/25776071
http://dx.doi.org/10.1161/HYP.0000000000000025
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