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


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Authors

Shaikh, Lalarukh Haris 
Zhou, Junhua 
Teo, Ada ED 
Garg, Sumedha 
Neogi, Sudeshna Guha 

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.

Description

Keywords

Adrenal Glands, Aldosterone, Cell Count, Down-Regulation, Gene Expression Profiling, Humans, Immunohistochemistry, Microarray Analysis, Receptors, G-Protein-Coupled, Tumor Cells, Cultured, Up-Regulation, Wnt Signaling Pathway, Zona Fasciculata, Zona Glomerulosa

Journal Title

J Clin Endocrinol Metab

Conference Name

Journal ISSN

0021-972X
1945-7197

Volume Title

100

Publisher

The Endocrine Society
Sponsorship
Wellcome Trust (085686/Z/08/A)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
Medical Research Council (MC_UU_12012/5)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
Medical Research Council (G1000847)
Medical Research Council (G0800784)
Medical Research Council (MC_UU_12012/5/B)
Medical Research Council (MC_PC_12012)
This work was supported by MJB is an NIHR Senior Investigator NF-SI-0512–10 052; LHS holds a British Heart Foundation PhD studentship FS/11/35/28871; JZ holds a Cambridge Overseas Trust Scholarship; AEDT is funded by the Wellcome Trust Translational Medicine and Therapeutics program 085 686/Z/08/A, and by Singapore A* program; EABA was supported by the Austin Doyle Award (Servier Australia); LHS, JZ and EABA were additionally supported by the NIHR Cambridge Biomedical Research Centre; GM are funded by MRC Programme Grants RDAG/287 and SKAG/001 awarded to Ashok Venkitaraman.