دورية أكاديمية
Physiological and Pathological Roles in Human Adrenal of the Glomeruli-Defining Matrix Protein NPNT (Nephronectin).
| العنوان: | Physiological and Pathological Roles in Human Adrenal of the Glomeruli-Defining Matrix Protein NPNT (Nephronectin). |
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| المؤلفون: | Teo AE; From the Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital (A.E.D.T., S.G., J.Z., M.J.B.), Tissue Bank, Department of Histopathology, Addenbrooke's Hospital (W.Z.), NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital (M.G.), MRC Cancer Unit, Hutchison/MRC Research Centre (T.I.J.), and Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science (M.G.), University of Cambridge, United Kingdom; 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.); Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Centre, Jackson (C.E.G.-S.); and Research and Medicine Services, G.V. (Sonny) Montgomery VA Medical Centre, Jackson, MS (C.E.G.-S.)., Garg S; From the Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital (A.E.D.T., S.G., J.Z., M.J.B.), Tissue Bank, Department of Histopathology, Addenbrooke's Hospital (W.Z.), NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital (M.G.), MRC Cancer Unit, Hutchison/MRC Research Centre (T.I.J.), and Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science (M.G.), University of Cambridge, United Kingdom; 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.); Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Centre, Jackson (C.E.G.-S.); and Research and Medicine Services, G.V. (Sonny) Montgomery VA Medical Centre, Jackson, MS (C.E.G.-S.)., Johnson TI; From the Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital (A.E.D.T., S.G., J.Z., M.J.B.), Tissue Bank, Department of Histopathology, Addenbrooke's Hospital (W.Z.), NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital (M.G.), MRC Cancer Unit, Hutchison/MRC Research Centre (T.I.J.), and Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science (M.G.), University of Cambridge, United Kingdom; 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.); Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Centre, Jackson (C.E.G.-S.); and Research and Medicine Services, G.V. (Sonny) Montgomery VA Medical Centre, Jackson, MS (C.E.G.-S.)., Zhao W; From the Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital (A.E.D.T., S.G., J.Z., M.J.B.), Tissue Bank, Department of Histopathology, Addenbrooke's Hospital (W.Z.), NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital (M.G.), MRC Cancer Unit, Hutchison/MRC Research Centre (T.I.J.), and Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science (M.G.), University of Cambridge, United Kingdom; 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.); Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Centre, Jackson (C.E.G.-S.); and Research and Medicine Services, G.V. (Sonny) Montgomery VA Medical Centre, Jackson, MS (C.E.G.-S.)., Zhou J; From the Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital (A.E.D.T., S.G., J.Z., M.J.B.), Tissue Bank, Department of Histopathology, Addenbrooke's Hospital (W.Z.), NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital (M.G.), MRC Cancer Unit, Hutchison/MRC Research Centre (T.I.J.), and Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science (M.G.), University of Cambridge, United Kingdom; 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.); Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Centre, Jackson (C.E.G.-S.); and Research and Medicine Services, G.V. (Sonny) Montgomery VA Medical Centre, Jackson, MS (C.E.G.-S.)., Gomez-Sanchez CE; From the Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital (A.E.D.T., S.G., J.Z., M.J.B.), Tissue Bank, Department of Histopathology, Addenbrooke's Hospital (W.Z.), NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital (M.G.), MRC Cancer Unit, Hutchison/MRC Research Centre (T.I.J.), and Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science (M.G.), University of Cambridge, United Kingdom; 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.); Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Centre, Jackson (C.E.G.-S.); and Research and Medicine Services, G.V. (Sonny) Montgomery VA Medical Centre, Jackson, MS (C.E.G.-S.)., Gurnell M; From the Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital (A.E.D.T., S.G., J.Z., M.J.B.), Tissue Bank, Department of Histopathology, Addenbrooke's Hospital (W.Z.), NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital (M.G.), MRC Cancer Unit, Hutchison/MRC Research Centre (T.I.J.), and Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science (M.G.), University of Cambridge, United Kingdom; 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.); Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Centre, Jackson (C.E.G.-S.); and Research and Medicine Services, G.V. (Sonny) Montgomery VA Medical Centre, Jackson, MS (C.E.G.-S.)., Brown MJ; From the Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital (A.E.D.T., S.G., J.Z., M.J.B.), Tissue Bank, Department of Histopathology, Addenbrooke's Hospital (W.Z.), NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital (M.G.), MRC Cancer Unit, Hutchison/MRC Research Centre (T.I.J.), and Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science (M.G.), University of Cambridge, United Kingdom; 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.); Division of Endocrinology, Department of Medicine, The University of Mississippi Medical Centre, Jackson (C.E.G.-S.); and Research and Medicine Services, G.V. (Sonny) Montgomery VA Medical Centre, Jackson, MS (C.E.G.-S.). morris.brown@qmul.ac.uk. |
| المصدر: | Hypertension (Dallas, Tex. : 1979) [Hypertension] 2017 Jun; Vol. 69 (6), pp. 1207-1216. Date of Electronic Publication: 2017 Apr 17. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Lippincott, Williams & Wilkins Country of Publication: United States NLM ID: 7906255 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4563 (Electronic) Linking ISSN: 0194911X NLM ISO Abbreviation: Hypertension Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Original Publication: [Dallas, Tex.] : [American Heart Association], [©1979]- |
| مواضيع طبية MeSH: | Gene Expression Regulation*, Adrenal Cortex Neoplasms/*genetics , Extracellular Matrix Proteins/*genetics , Hyperaldosteronism/*genetics , Kidney Glomerulus/*metabolism, Adrenal Cortex/metabolism ; Adrenal Cortex Neoplasms/pathology ; Adrenal Cortex Neoplasms/surgery ; Aldosterone/blood ; Cytochrome P-450 CYP11B2/metabolism ; Humans ; Hyperaldosteronism/pathology ; Hyperaldosteronism/surgery ; Hypertension/genetics ; Hypertension/physiopathology ; Immunohistochemistry ; Microarray Analysis ; Real-Time Polymerase Chain Reaction/methods ; Role ; Tumor Cells, Cultured ; Up-Regulation ; Wnt Signaling Pathway/genetics ; Zona Glomerulosa/metabolism |
| مستخلص: | Primary aldosteronism is a common cause of hypertension, which becomes refractory if undiagnosed, but potentially curable when caused by an aldosterone-producing adenoma (APA). The discovery of somatic mutations and differences in clinical presentations led to recognition of small but common zona glomerulosa (ZG)-like adenomas, distinct from classical large zona fasciculata-like adenomas. The inverse correlation between APA size and aldosterone synthase expression prompted us to undertake a systematic study of genotype-phenotype relationships. After a microarray comparing tumor subtypes, in which NPNT ( nephronectin ) was the most highly (>12-fold) upregulated gene in ZG-like APAs, we aimed to determine its role in physiological and pathological aldosterone production. NPNT was identified by immunohistochemistry as a secreted matrix protein expressed exclusively around aldosterone-producing glomeruli in normal adrenal ZG and in aldosterone-dense ZG-like APAs; the highest expression was in ZG-like APAs with gain-of-function CTNNB1 mutations, whose removal cured hypertension in our patients. NPNT was absent from normal zona fasciculata, zona fasciculata-like APAs, and ZG adjacent to an APA. NPNT production was regulated by canonical Wnt pathway, and NPNT overexpression or silencing increased or reduced aldosterone, respectively. NPNT was proadhesive in primary adrenal and APA cells but antiadhesive and antiapoptotic in immortalized adrenocortical cells. The discovery of NPNT in the adrenal helped recognition of a common subtype of APAs and a pathway by which Wnt regulates aldosterone production. We propose that this arises through NPNT's binding to cell-surface integrins, stimulating cell-cell contact within glomeruli, which define ZG. Therefore, NPNT or its cognate integrin could present a novel therapeutic target. (© 2017 The Authors.) |
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| معلومات مُعتمدة: | 085686 United Kingdom Wellcome Trust; FS/14/75/31134 United Kingdom British Heart Foundation |
| فهرسة مساهمة: | Keywords: Wnt signaling pathway; adenoma; aldosterone; extracellular matrix; hypertension |
| المشرفين على المادة: | 0 (Extracellular Matrix Proteins) 0 (nephronectin) 4964P6T9RB (Aldosterone) EC 1.14.15.4 (Cytochrome P-450 CYP11B2) |
| تواريخ الأحداث: | Date Created: 20170419 Date Completed: 20170816 Latest Revision: 20240531 |
| رمز التحديث: | 20240531 |
| مُعرف محوري في PubMed: | PMC5424579 |
| DOI: | 10.1161/HYPERTENSIONAHA.117.09156 |
| PMID: | 28416583 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1524-4563 |
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| DOI: | 10.1161/HYPERTENSIONAHA.117.09156 |