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

Zhou J 1 , Lam B 1 , Neogi SG 1 , Yeo GS 1 , Azizan EA 2 , Brown MJ 1

Affiliations 

  • 1 From the Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, United Kingdom (J.Z., M.J.B.); Clinical Pharmacology Unit, Department of Medicine, University of Cambridge (J.Z.), University of Cambridge Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science (B.L., G.S.H.Y.), Cambridge University Hospitals NHS Foundation Trust (S.G.N.), Addenbrooke's Hospital, United Kingdom; and Department of Medicine, Faculty of Medicine, The National University of Malaysia (UKM) Medical Centre, Kuala Lumpur (E.A.B.A.)
  • 2 From the Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, United Kingdom (J.Z., M.J.B.); Clinical Pharmacology Unit, Department of Medicine, University of Cambridge (J.Z.), University of Cambridge Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science (B.L., G.S.H.Y.), Cambridge University Hospitals NHS Foundation Trust (S.G.N.), Addenbrooke's Hospital, United Kingdom; and Department of Medicine, Faculty of Medicine, The National University of Malaysia (UKM) Medical Centre, Kuala Lumpur (E.A.B.A.). [email protected]
Hypertension, 2016 12;68(6):1424-1431.
PMID: 27777363

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

MeSH terms
Similar publications