Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | E836-E844 |
| Journal | Journal of Clinical Endocrinology and Metabolism |
| Volume | 100 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 1 Jun 2015 |
Fingerprint
ASJC Scopus subject areas
- Biochemistry
- Clinical Biochemistry
- Endocrinology
- Biochemistry, medical
- Endocrinology, Diabetes and Metabolism
Cite this
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.; Elena Aisha, Azizan; Davenport, Anthony P.; McKenzie, Grahame; Brown, Morris J.
In: Journal of Clinical Endocrinology and Metabolism, Vol. 100, No. 6, 01.06.2015, p. E836-E844.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - LGR5 activates noncanonical Wnt signaling and inhibits aldosterone production in the human adrenal
AU - Shaikh, Lalarukh Haris
AU - Zhou, Junhua
AU - Teo, Ada E D
AU - Garg, Sumedha
AU - Neogi, Sudeshna Guha
AU - Figg, Nichola
AU - Yeo, Giles S.
AU - Yu, Haixiang
AU - Maguire, Janet J.
AU - Zhao, Wanfeng
AU - Bennett, Martin R.
AU - Elena Aisha, Azizan
AU - Davenport, Anthony P.
AU - McKenzie, Grahame
AU - Brown, Morris J.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84930806876&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930806876&partnerID=8YFLogxK
U2 - 10.1210/jc.2015-1734
DO - 10.1210/jc.2015-1734
M3 - Article
C2 - 25915569
AN - SCOPUS:84930806876
VL - 100
SP - E836-E844
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 6
ER -