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.
authors: 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.).
authors: Junhua
authors: J
authors: Zhou
authors: 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.).
authors: Brian
authors: B
authors: Lam
authors: 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.).
authors: Sudeshna G
authors: SG
authors: Neogi
authors: 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.).
authors: Giles S H
authors: GS
authors: Yeo
authors: 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.). elena.azizan@ukm.edu.my.
authors: Elena A B
authors: EA
authors: Azizan
authors: 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.).
authors: Morris J
authors: MJ
authors: Brown
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000503:physiopathology; D000302:Adrenal Cortex / Q000473:pathology / Q000502:physiology; D000450:Aldosterone / Q000378:metabolism*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics* / Q000503:physiopathology; D010673:Pheochromocytoma / Q000235:genetics / Q000503:physiopathology; D012494:Sampling Studies; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D015383:Zona Fasciculata / Q000378:metabolism; D015384:Zona Glomerulosa / Q000378:metabolism
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D014157:Transcription Factors; D000450:Aldosterone
keywords: aldosterone; gene ontology; primary hyperaldosteronism; zona fasciculata; zona glomerulosa