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2015 ; 65
(5
): 1103-10
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DACH1, a zona glomerulosa selective gene in the human adrenal, activates
transforming growth factor-? signaling and suppresses aldosterone secretion
#MMPMID25776071
Zhou J
; Shaikh LH
; Neogi SG
; McFarlane I
; Zhao W
; Figg N
; Brighton CA
; Maniero C
; Teo AE
; Azizan EA
; Brown MJ
Hypertension
2015[May]; 65
(5
): 1103-10
PMID25776071
show ga
Common somatic mutations in CACNAID and ATP1A1 may define a subgroup of smaller,
zona glomerulosa (ZG)-like aldosterone-producing adenomas. We have therefore
sought signature ZG genes, which may provide insight into the frequency and
pathogenesis of ZG-like aldosterone-producing adenomas. Twenty-one pairs of zona
fasciculata and ZG and 14 paired aldosterone-producing adenomas from 14 patients
with Conn's syndrome and 7 patients with pheochromocytoma were assayed by the
Affymetrix Human Genome U133 Plus 2.0 Array. Validation by quantitative real-time
polymerase chain reaction was performed on genes >10-fold upregulated in ZG
(compared with zona fasciculata) and >10-fold upregulated in
aldosterone-producing adenomas (compared with ZG). DACH1, a gene associated with
tumor progression, was further analyzed. The role of DACH1 on steroidogenesis,
transforming growth factor-?, and Wnt signaling activity was assessed in the
human adrenocortical cell line, H295R. Immunohistochemistry confirmed selective
expression of DACH1 in human ZG. Silencing of DACH1 in H295R cells increased
CYP11B2 mRNA levels and aldosterone production, whereas overexpression of DACH1
decreased aldosterone production. Overexpression of DACH1 in H295R cells
activated the transforming growth factor-? and canonical Wnt signaling pathways
but inhibited the noncanonical Wnt signaling pathway. Stimulation of primary
human adrenal cells with angiotensin II decreased DACH1 mRNA expression.
Interestingly, there was little overlap between our top ZG genes and those in
rodent ZG. In conclusion, (1) the transcriptome profile of human ZG differs from
rodent ZG, (2) DACH1 inhibits aldosterone secretion in human adrenals, and (3)
transforming growth factor-? signaling pathway is activated in DACH1
overexpressed cells and may mediate inhibition of aldosterone secretion in human
adrenals.