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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.
Highlights
IntroductionSince their discovery by Conn nearly 60 years ago, APAs have been regarded as infrequent ‒ less than 1%
Since their discovery by Conn nearly 60 years ago, APAs have been regarded as infrequent ‒ less than 1%of all hypertension; recent estimates of prevalence, have risen to several times this figure [1].Most APAs, though, are diagnosed too late for complete cure of hypertension [2], and there is a need for better-tolerated drugs that block the increased aldosterone production
LGR5 and several other genes associated with the Wnt signaling pathway are selectively and abundantly expressed in human adrenal ZG
Summary
Since their discovery by Conn nearly 60 years ago, APAs have been regarded as infrequent ‒ less than 1%. Most APAs, though, are diagnosed too late for complete cure of hypertension [2], and there is a need for better-tolerated drugs that block the increased aldosterone production. In addition to limitations of efficacy or selectivity, such drugs increase aldosterone production [3]. Novel drug targets can be identified by the discovery of either a gene whose gain-of-function mutation increases aldosterone production in APAs, or pathways coupled to inhibition of aldosterone in the normal adrenal. APAs are often a heterogeneous mixture of cells; paradoxically, the cells of classical Conn’s tumours appear more like cortisol-producing ZF cells than the supposedly aldosterone-producing cells of normal
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