Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1782374658429943808 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4454794 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Endocrine Society |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT shaikhlalarukhharis lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT zhoujunhua lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT teoadaed lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT gargsumedha lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT neogisudeshnaguha lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT figgnichola lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT yeogiless lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT yuhaixiang lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT maguirejanetj lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT zhaowanfeng lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT bennettmartinr lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT azizanelenaab lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT davenportanthonyp lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT mckenziegrahame lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal AT brownmorrisj lgr5activatesnoncanonicalwntsignalingandinhibitsaldosteroneproductioninthehumanadrenal |