DACH1, a zona glomerulosa selective gene in the human adrenal, activates transforming growth factor-β signaling and suppresses aldosterone secretion

Junhua Zhou, Lalarukh Haris Shaikh, Sudeshna G. Neogi, Ian Mcfarlane, Wanfeng Zhao, Nichola Figg, Cheryl A. Brighton, Carmela Maniero, Ada E D Teo, Azizan Elena Aisha, Morris J. Brown

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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-β, 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-β 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-β signaling pathway is activated in DACH1 overexpressed cells and may mediate inhibition of aldosterone secretion in human adrenals.

Original languageEnglish
Pages (from-to)1103-1110
Number of pages8
JournalHypertension
Volume65
Issue number5
DOIs
Publication statusPublished - 21 May 2015

Fingerprint

Zona Glomerulosa
Transforming Growth Factors
Aldosterone
Genes
Adenoma
Wnt Signaling Pathway
Zona Fasciculata
Rodentia
Cytochrome P-450 CYP11B2
Messenger RNA
Hyperaldosteronism
Pheochromocytoma
Human Genome
Transcriptome
Angiotensin II
Real-Time Polymerase Chain Reaction
Immunohistochemistry

Keywords

  • aldosterone
  • DACH1 protein human
  • hyperaldosteronism
  • transforming growth factor beta
  • zona glomerulosa

ASJC Scopus subject areas

  • Internal Medicine

Cite this

DACH1, a zona glomerulosa selective gene in the human adrenal, activates transforming growth factor-β signaling and suppresses aldosterone secretion. / Zhou, Junhua; Shaikh, Lalarukh Haris; Neogi, Sudeshna G.; Mcfarlane, Ian; Zhao, Wanfeng; Figg, Nichola; Brighton, Cheryl A.; Maniero, Carmela; Teo, Ada E D; Elena Aisha, Azizan; Brown, Morris J.

In: Hypertension, Vol. 65, No. 5, 21.05.2015, p. 1103-1110.

Research output: Contribution to journalArticle

Zhou, J, Shaikh, LH, Neogi, SG, Mcfarlane, I, Zhao, W, Figg, N, Brighton, CA, Maniero, C, Teo, AED, Elena Aisha, A & Brown, MJ 2015, 'DACH1, a zona glomerulosa selective gene in the human adrenal, activates transforming growth factor-β signaling and suppresses aldosterone secretion', Hypertension, vol. 65, no. 5, pp. 1103-1110. https://doi.org/10.1161/HYP.0000000000000025
Zhou, Junhua ; Shaikh, Lalarukh Haris ; Neogi, Sudeshna G. ; Mcfarlane, Ian ; Zhao, Wanfeng ; Figg, Nichola ; Brighton, Cheryl A. ; Maniero, Carmela ; Teo, Ada E D ; Elena Aisha, Azizan ; Brown, Morris J. / DACH1, a zona glomerulosa selective gene in the human adrenal, activates transforming growth factor-β signaling and suppresses aldosterone secretion. In: Hypertension. 2015 ; Vol. 65, No. 5. pp. 1103-1110.
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abstract = "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-β, 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-β 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-β signaling pathway is activated in DACH1 overexpressed cells and may mediate inhibition of aldosterone secretion in human adrenals.",
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