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LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal

CONTEXT: Aldosterone synthesis and cellularity in the human adrenal zona glomerulosa (ZG) is sparse and patchy, presumably due to salt excess. The frequency of somatic mutations causing aldosterone-producing adenomas (APAs) may be a consequence of protection from cell loss by constitutive aldosteron...

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Autores principales: Shaikh, Lalarukh Haris, Zhou, Junhua, Teo, Ada E. D., Garg, Sumedha, Neogi, Sudeshna Guha, Figg, Nichola, Yeo, Giles S., Yu, Haixiang, Maguire, Janet J., Zhao, Wanfeng, Bennett, Martin R., Azizan, Elena A. B., Davenport, Anthony P., McKenzie, Grahame, Brown, Morris J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Endocrine Society 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454794/
https://www.ncbi.nlm.nih.gov/pubmed/25915569
http://dx.doi.org/10.1210/jc.2015-1734
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author Shaikh, Lalarukh Haris
Zhou, Junhua
Teo, Ada E. D.
Garg, Sumedha
Neogi, Sudeshna Guha
Figg, Nichola
Yeo, Giles S.
Yu, Haixiang
Maguire, Janet J.
Zhao, Wanfeng
Bennett, Martin R.
Azizan, Elena A. B.
Davenport, Anthony P.
McKenzie, Grahame
Brown, Morris J.
author_facet Shaikh, Lalarukh Haris
Zhou, Junhua
Teo, Ada E. D.
Garg, Sumedha
Neogi, Sudeshna Guha
Figg, Nichola
Yeo, Giles S.
Yu, Haixiang
Maguire, Janet J.
Zhao, Wanfeng
Bennett, Martin R.
Azizan, Elena A. B.
Davenport, Anthony P.
McKenzie, Grahame
Brown, Morris J.
author_sort Shaikh, Lalarukh Haris
collection PubMed
description CONTEXT: Aldosterone synthesis and cellularity in the human adrenal zona glomerulosa (ZG) is sparse and patchy, presumably due to salt excess. The frequency of somatic mutations causing aldosterone-producing adenomas (APAs) may be a consequence of protection from cell loss by constitutive aldosterone production. OBJECTIVE: The objective of the study was to delineate a process in human ZG, which may regulate both aldosterone production and cell turnover. DESIGN: This study included a comparison of 20 pairs of ZG and zona fasciculata transcriptomes from adrenals adjacent to an APA (n = 13) or a pheochromocytoma (n = 7). INTERVENTIONS: Interventions included an overexpression of the top ZG gene (LGR5) or stimulation by its ligand (R-spondin-3). MAIN OUTCOME MEASURES: A transcriptome profile of ZG and zona fasciculata and aldosterone production, cell kinetic measurements, and Wnt signaling activity of LGR5 transfected or R-spondin-3-stimulated cells were measured. RESULTS: LGR5 was the top gene up-regulated in ZG (25-fold). The gene for its cognate ligand R-spondin-3, RSPO3, was 5-fold up-regulated. In total, 18 genes associated with the Wnt pathway were greater than 2-fold up-regulated. ZG selectivity of LGR5, and its absence in most APAs, were confirmed by quantitative PCR and immunohistochemistry. Both R-spondin-3 stimulation and LGR5 transfection of human adrenal cells suppressed aldosterone production. There was reduced proliferation and increased apoptosis of transfected cells, and the noncanonical activator protein-1/Jun pathway was stimulated more than the canonical Wnt pathway (3-fold vs 1.3-fold). ZG of adrenal sections stained positive for apoptosis markers. CONCLUSION: LGR5 is the most selectively expressed gene in human ZG and reduces aldosterone production and cell number. Such conditions may favor cells whose somatic mutation reverses aldosterone inhibition and cell loss.
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spelling pubmed-44547942015-06-22 LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal Shaikh, Lalarukh Haris Zhou, Junhua Teo, Ada E. D. Garg, Sumedha Neogi, Sudeshna Guha Figg, Nichola Yeo, Giles S. Yu, Haixiang Maguire, Janet J. Zhao, Wanfeng Bennett, Martin R. Azizan, Elena A. B. Davenport, Anthony P. McKenzie, Grahame Brown, Morris J. J Clin Endocrinol Metab Hot Topics in Translational Endocrinology CONTEXT: Aldosterone synthesis and cellularity in the human adrenal zona glomerulosa (ZG) is sparse and patchy, presumably due to salt excess. The frequency of somatic mutations causing aldosterone-producing adenomas (APAs) may be a consequence of protection from cell loss by constitutive aldosterone production. OBJECTIVE: The objective of the study was to delineate a process in human ZG, which may regulate both aldosterone production and cell turnover. DESIGN: This study included a comparison of 20 pairs of ZG and zona fasciculata transcriptomes from adrenals adjacent to an APA (n = 13) or a pheochromocytoma (n = 7). INTERVENTIONS: Interventions included an overexpression of the top ZG gene (LGR5) or stimulation by its ligand (R-spondin-3). MAIN OUTCOME MEASURES: A transcriptome profile of ZG and zona fasciculata and aldosterone production, cell kinetic measurements, and Wnt signaling activity of LGR5 transfected or R-spondin-3-stimulated cells were measured. RESULTS: LGR5 was the top gene up-regulated in ZG (25-fold). The gene for its cognate ligand R-spondin-3, RSPO3, was 5-fold up-regulated. In total, 18 genes associated with the Wnt pathway were greater than 2-fold up-regulated. ZG selectivity of LGR5, and its absence in most APAs, were confirmed by quantitative PCR and immunohistochemistry. Both R-spondin-3 stimulation and LGR5 transfection of human adrenal cells suppressed aldosterone production. There was reduced proliferation and increased apoptosis of transfected cells, and the noncanonical activator protein-1/Jun pathway was stimulated more than the canonical Wnt pathway (3-fold vs 1.3-fold). ZG of adrenal sections stained positive for apoptosis markers. CONCLUSION: LGR5 is the most selectively expressed gene in human ZG and reduces aldosterone production and cell number. Such conditions may favor cells whose somatic mutation reverses aldosterone inhibition and cell loss. Endocrine Society 2015-06 2015-04-27 /pmc/articles/PMC4454794/ /pubmed/25915569 http://dx.doi.org/10.1210/jc.2015-1734 Text en https://creativecommons.org/licenses/by/4.0/ This article has been published under the terms of the Creative Commons Attribution License (CC-BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s).
spellingShingle Hot Topics in Translational Endocrinology
Shaikh, Lalarukh Haris
Zhou, Junhua
Teo, Ada E. D.
Garg, Sumedha
Neogi, Sudeshna Guha
Figg, Nichola
Yeo, Giles S.
Yu, Haixiang
Maguire, Janet J.
Zhao, Wanfeng
Bennett, Martin R.
Azizan, Elena A. B.
Davenport, Anthony P.
McKenzie, Grahame
Brown, Morris J.
LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal
title LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal
title_full LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal
title_fullStr LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal
title_full_unstemmed LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal
title_short LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal
title_sort lgr5 activates noncanonical wnt signaling and inhibits aldosterone production in the human adrenal
topic Hot Topics in Translational Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454794/
https://www.ncbi.nlm.nih.gov/pubmed/25915569
http://dx.doi.org/10.1210/jc.2015-1734
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