Transcriptome Pathway Analysis of Pathological and Physiological Aldosterone-Producing Human Tissues

Junhua Zhou, Brian Lam, Sudeshna G. Neogi, Giles S H Yeo, Azizan Elena Aisha, Morris J. Brown

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Primary aldosteronism is present in ≈10% of hypertensives. We previously performed a microarray assay on aldosterone-producing adenomas and their paired zona glomerulosa and fasciculata. Confirmation of top genes validated the study design and functional experiments of zona glomerulosa selective genes established the role of the encoded proteins in aldosterone regulation. In this study, we further analyzed our microarray data using AmiGO 2 for gene ontology enrichment and Ingenuity Pathway Analysis to identify potential biological processes and canonical pathways involved in pathological and physiological aldosterone regulation. Genes differentially regulated in aldosterone-producing adenoma and zona glomerulosa were associated with steroid metabolic processes gene ontology terms. Terms related to the Wnt signaling pathway were enriched in zona glomerulosa only. Ingenuity Pathway Analysis showed "NRF2-mediated oxidative stress response pathway" and "LPS (lipopolysaccharide)/IL-1 (interleukin-1)-mediated inhibition of RXR (retinoid X receptor) function" were affected in both aldosterone-producing adenoma and zona glomerulosa with associated genes having up to 21- and 8-fold differences, respectively. Comparing KCNJ5-mutant aldosterone-producing adenoma, zona glomerulosa, and zona fasciculata samples with wild-type samples, 138, 56, and 59 genes were differentially expressed, respectively (fold-change >2; P<0.05). ACSS3, encoding the enzyme that synthesizes acetyl-CoA, was the top gene upregulated in KCNJ5-mutant aldosterone-producing adenoma compared with wild-type. NEFM, a gene highly upregulated in zona glomerulosa, was upregulated in KCNJ5 wild-type aldosterone-producing adenomas. NR4A2, the transcription factor for aldosterone synthase, was highly expressed in zona fasciculata adjacent to a KCNJ5-mutant aldosterone-producing adenoma. Further interrogation of these genes and pathways could potentially provide further insights into the pathology of primary aldosteronism.

Original languageEnglish
Pages (from-to)1424-1431
Number of pages8
JournalHypertension
Volume68
Issue number6
DOIs
Publication statusPublished - 1 Dec 2016

Fingerprint

Gene Expression Profiling
Zona Glomerulosa
Aldosterone
Adenoma
Zona Fasciculata
Genes
Gene Ontology
Hyperaldosteronism
Interleukin-1
Cytochrome P-450 CYP11B2
Retinoid X Receptors
Biological Phenomena
Acetyl Coenzyme A
Wnt Signaling Pathway
Lipopolysaccharides
Oxidative Stress
Transcription Factors
Steroids
Pathology
Enzymes

Keywords

  • aldosterone
  • gene ontology
  • primary hyperaldosteronism
  • zona fasciculata
  • zona glomerulosa

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Transcriptome Pathway Analysis of Pathological and Physiological Aldosterone-Producing Human Tissues. / Zhou, Junhua; Lam, Brian; Neogi, Sudeshna G.; Yeo, Giles S H; Elena Aisha, Azizan; Brown, Morris J.

In: Hypertension, Vol. 68, No. 6, 01.12.2016, p. 1424-1431.

Research output: Contribution to journalArticle

Zhou, Junhua ; Lam, Brian ; Neogi, Sudeshna G. ; Yeo, Giles S H ; Elena Aisha, Azizan ; Brown, Morris J. / Transcriptome Pathway Analysis of Pathological and Physiological Aldosterone-Producing Human Tissues. In: Hypertension. 2016 ; Vol. 68, No. 6. pp. 1424-1431.
@article{ce0ff9fff41049c0b8272825c0bbe093,
title = "Transcriptome Pathway Analysis of Pathological and Physiological Aldosterone-Producing Human Tissues",
abstract = "Primary aldosteronism is present in ≈10{\%} of hypertensives. We previously performed a microarray assay on aldosterone-producing adenomas and their paired zona glomerulosa and fasciculata. Confirmation of top genes validated the study design and functional experiments of zona glomerulosa selective genes established the role of the encoded proteins in aldosterone regulation. In this study, we further analyzed our microarray data using AmiGO 2 for gene ontology enrichment and Ingenuity Pathway Analysis to identify potential biological processes and canonical pathways involved in pathological and physiological aldosterone regulation. Genes differentially regulated in aldosterone-producing adenoma and zona glomerulosa were associated with steroid metabolic processes gene ontology terms. Terms related to the Wnt signaling pathway were enriched in zona glomerulosa only. Ingenuity Pathway Analysis showed {"}NRF2-mediated oxidative stress response pathway{"} and {"}LPS (lipopolysaccharide)/IL-1 (interleukin-1)-mediated inhibition of RXR (retinoid X receptor) function{"} were affected in both aldosterone-producing adenoma and zona glomerulosa with associated genes having up to 21- and 8-fold differences, respectively. Comparing KCNJ5-mutant aldosterone-producing adenoma, zona glomerulosa, and zona fasciculata samples with wild-type samples, 138, 56, and 59 genes were differentially expressed, respectively (fold-change >2; P<0.05). ACSS3, encoding the enzyme that synthesizes acetyl-CoA, was the top gene upregulated in KCNJ5-mutant aldosterone-producing adenoma compared with wild-type. NEFM, a gene highly upregulated in zona glomerulosa, was upregulated in KCNJ5 wild-type aldosterone-producing adenomas. NR4A2, the transcription factor for aldosterone synthase, was highly expressed in zona fasciculata adjacent to a KCNJ5-mutant aldosterone-producing adenoma. Further interrogation of these genes and pathways could potentially provide further insights into the pathology of primary aldosteronism.",
keywords = "aldosterone, gene ontology, primary hyperaldosteronism, zona fasciculata, zona glomerulosa",
author = "Junhua Zhou and Brian Lam and Neogi, {Sudeshna G.} and Yeo, {Giles S H} and {Elena Aisha}, Azizan and Brown, {Morris J.}",
year = "2016",
month = "12",
day = "1",
doi = "10.1161/HYPERTENSIONAHA.116.08033",
language = "English",
volume = "68",
pages = "1424--1431",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - Transcriptome Pathway Analysis of Pathological and Physiological Aldosterone-Producing Human Tissues

AU - Zhou, Junhua

AU - Lam, Brian

AU - Neogi, Sudeshna G.

AU - Yeo, Giles S H

AU - Elena Aisha, Azizan

AU - Brown, Morris J.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Primary aldosteronism is present in ≈10% of hypertensives. We previously performed a microarray assay on aldosterone-producing adenomas and their paired zona glomerulosa and fasciculata. Confirmation of top genes validated the study design and functional experiments of zona glomerulosa selective genes established the role of the encoded proteins in aldosterone regulation. In this study, we further analyzed our microarray data using AmiGO 2 for gene ontology enrichment and Ingenuity Pathway Analysis to identify potential biological processes and canonical pathways involved in pathological and physiological aldosterone regulation. Genes differentially regulated in aldosterone-producing adenoma and zona glomerulosa were associated with steroid metabolic processes gene ontology terms. Terms related to the Wnt signaling pathway were enriched in zona glomerulosa only. Ingenuity Pathway Analysis showed "NRF2-mediated oxidative stress response pathway" and "LPS (lipopolysaccharide)/IL-1 (interleukin-1)-mediated inhibition of RXR (retinoid X receptor) function" were affected in both aldosterone-producing adenoma and zona glomerulosa with associated genes having up to 21- and 8-fold differences, respectively. Comparing KCNJ5-mutant aldosterone-producing adenoma, zona glomerulosa, and zona fasciculata samples with wild-type samples, 138, 56, and 59 genes were differentially expressed, respectively (fold-change >2; P<0.05). ACSS3, encoding the enzyme that synthesizes acetyl-CoA, was the top gene upregulated in KCNJ5-mutant aldosterone-producing adenoma compared with wild-type. NEFM, a gene highly upregulated in zona glomerulosa, was upregulated in KCNJ5 wild-type aldosterone-producing adenomas. NR4A2, the transcription factor for aldosterone synthase, was highly expressed in zona fasciculata adjacent to a KCNJ5-mutant aldosterone-producing adenoma. Further interrogation of these genes and pathways could potentially provide further insights into the pathology of primary aldosteronism.

AB - Primary aldosteronism is present in ≈10% of hypertensives. We previously performed a microarray assay on aldosterone-producing adenomas and their paired zona glomerulosa and fasciculata. Confirmation of top genes validated the study design and functional experiments of zona glomerulosa selective genes established the role of the encoded proteins in aldosterone regulation. In this study, we further analyzed our microarray data using AmiGO 2 for gene ontology enrichment and Ingenuity Pathway Analysis to identify potential biological processes and canonical pathways involved in pathological and physiological aldosterone regulation. Genes differentially regulated in aldosterone-producing adenoma and zona glomerulosa were associated with steroid metabolic processes gene ontology terms. Terms related to the Wnt signaling pathway were enriched in zona glomerulosa only. Ingenuity Pathway Analysis showed "NRF2-mediated oxidative stress response pathway" and "LPS (lipopolysaccharide)/IL-1 (interleukin-1)-mediated inhibition of RXR (retinoid X receptor) function" were affected in both aldosterone-producing adenoma and zona glomerulosa with associated genes having up to 21- and 8-fold differences, respectively. Comparing KCNJ5-mutant aldosterone-producing adenoma, zona glomerulosa, and zona fasciculata samples with wild-type samples, 138, 56, and 59 genes were differentially expressed, respectively (fold-change >2; P<0.05). ACSS3, encoding the enzyme that synthesizes acetyl-CoA, was the top gene upregulated in KCNJ5-mutant aldosterone-producing adenoma compared with wild-type. NEFM, a gene highly upregulated in zona glomerulosa, was upregulated in KCNJ5 wild-type aldosterone-producing adenomas. NR4A2, the transcription factor for aldosterone synthase, was highly expressed in zona fasciculata adjacent to a KCNJ5-mutant aldosterone-producing adenoma. Further interrogation of these genes and pathways could potentially provide further insights into the pathology of primary aldosteronism.

KW - aldosterone

KW - gene ontology

KW - primary hyperaldosteronism

KW - zona fasciculata

KW - zona glomerulosa

UR - http://www.scopus.com/inward/record.url?scp=84992416425&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84992416425&partnerID=8YFLogxK

U2 - 10.1161/HYPERTENSIONAHA.116.08033

DO - 10.1161/HYPERTENSIONAHA.116.08033

M3 - Article

C2 - 27777363

AN - SCOPUS:84992416425

VL - 68

SP - 1424

EP - 1431

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 6

ER -