NEFM (Neurofilament Medium) Polypeptide, a Marker for Zona Glomerulosa Cells in Human Adrenal, Inhibits D1R (Dopamine D1 Receptor)-Mediated Secretion of Aldosterone.
Autor: | Maniero C; From the Clinical Pharmacology Unit, Department of Medicine (C.M., S.G., J.Z.) and Medical Research Council Cancer Unit (T.I.J.), University of Cambridge, United Kingdom; Human Research Tissue Bank, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, United Kingdom (W.Z.); Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom (M.G.); and the Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (J.Z., M.J.B.)., Garg S; From the Clinical Pharmacology Unit, Department of Medicine (C.M., S.G., J.Z.) and Medical Research Council Cancer Unit (T.I.J.), University of Cambridge, United Kingdom; Human Research Tissue Bank, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, United Kingdom (W.Z.); Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom (M.G.); and the Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (J.Z., M.J.B.)., Zhao W; From the Clinical Pharmacology Unit, Department of Medicine (C.M., S.G., J.Z.) and Medical Research Council Cancer Unit (T.I.J.), University of Cambridge, United Kingdom; Human Research Tissue Bank, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, United Kingdom (W.Z.); Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom (M.G.); and the Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (J.Z., M.J.B.)., Johnson TI; From the Clinical Pharmacology Unit, Department of Medicine (C.M., S.G., J.Z.) and Medical Research Council Cancer Unit (T.I.J.), University of Cambridge, United Kingdom; Human Research Tissue Bank, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, United Kingdom (W.Z.); Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom (M.G.); and the Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (J.Z., M.J.B.)., Zhou J; From the Clinical Pharmacology Unit, Department of Medicine (C.M., S.G., J.Z.) and Medical Research Council Cancer Unit (T.I.J.), University of Cambridge, United Kingdom; Human Research Tissue Bank, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, United Kingdom (W.Z.); Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom (M.G.); and the Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (J.Z., M.J.B.)., Gurnell M; From the Clinical Pharmacology Unit, Department of Medicine (C.M., S.G., J.Z.) and Medical Research Council Cancer Unit (T.I.J.), University of Cambridge, United Kingdom; Human Research Tissue Bank, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, United Kingdom (W.Z.); Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom (M.G.); and the Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (J.Z., M.J.B.)., Brown MJ; From the Clinical Pharmacology Unit, Department of Medicine (C.M., S.G., J.Z.) and Medical Research Council Cancer Unit (T.I.J.), University of Cambridge, United Kingdom; Human Research Tissue Bank, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, United Kingdom (W.Z.); Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom (M.G.); and the Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (J.Z., M.J.B.). morris.brown@qmul.ac.uk. |
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Jazyk: | angličtina |
Zdroj: | Hypertension (Dallas, Tex. : 1979) [Hypertension] 2017 Aug; Vol. 70 (2), pp. 357-364. Date of Electronic Publication: 2017 Jun 05. |
DOI: | 10.1161/HYPERTENSIONAHA.117.09231 |
Abstrakt: | Heterogeneity among aldosterone-producing adenomas (APAs) has been highlighted by the discovery of somatic mutations. KCNJ5 mutations predominate in large zona fasciculata (ZF)-like APAs; mutations in CACNA1D , ATP1A1, ATP2B3 , and CTNNB1 are more likely to be found in small zona glomerulosa (ZG)-like APAs. Microarray comparison of KCNJ5 mutant versus wild-type APAs revealed significant differences in transcriptomes. NEFM , encoding a neurofilament subunit which is a D1R (dopamine D1 receptor)-interacting protein, was 4-fold upregulated in ZG-like versus ZF-like APAs and 14-fold more highly expressed in normal ZG versus ZF. Immunohistochemistry confirmed selective expression of NEFM (neurofilament medium) polypeptide in ZG and in ZG-like APAs. Silencing NEFM in adrenocortical H295R cells increased basal aldosterone secretion and cell proliferation; silencing also amplified aldosterone stimulation by the D1R agonist, fenoldopam, and inhibition by the D1R antagonist, SCH23390. NEFM coimmunoprecipitated with D1R, and its expression was stimulated by fenoldopam. Immunohistochemistry for D1R was mainly intracellular in ZG-like APAs but membranous in ZF-like APAs. Aldosterone secretion in response to fenoldopam in primary cells from ZF-like APAs was higher than in cells from ZG-like APAs. Transfection of mutant KCNJ5 caused a large reduction in NEFM expression in H295R cells. We conclude that NEFM is a negative regulator of aldosterone production and cell proliferation, in part by facilitating D1R internalization from the plasma membrane. Downregulation of NEFM in ZF-like APAs may contribute to a D1R/D2R imbalance underlying variable pharmacological responses to dopaminergic drugs among patients with APAs. Finally, taken together, our data point to the possibility that ZF-like APAs are in fact ZG in origin. (© 2017 American Heart Association, Inc.) |
Databáze: | MEDLINE |
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