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dc.contributor.authorManiero, Carmelaen
dc.contributor.authorGarg, Sen
dc.contributor.authorZhao, Wen
dc.contributor.authorJohnson, TIen
dc.contributor.authorZhou, Jen
dc.contributor.authorGurnell, Marken
dc.contributor.authorBrown, MJen
dc.date.accessioned2017-08-18T14:16:42Z
dc.date.available2017-08-18T14:16:42Z
dc.date.issued2017-08en
dc.identifier.issn0194-911X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/266639
dc.description.abstractHeterogeneity 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.
dc.description.sponsorshipThe work was funded by a National Institute for Health Research (NIHR) Senior Investigator Award [NF-SI-0512-10052] to M.J. Brown. C. Maniero was supported by a British Heart Foundation clinical research fellowship grant [FS/14/12/30540]. S. Garg was supported by a British Heart Foundation PhD scholarship [FS/14/75/31134]. J. Zhou was supported by the Cambridge Overseas Trust Scholarship and the Sun Hung Kai Properties-Kwoks’ Foundation and further supported by the NIHR Cambridge Biomedical Research Centre. M. Gurnell was funded by NIHR Cambridge Biomedical Research Centre (Metabolic). T.I. Johnson was funded by the Medical Research Council. The IMS Imaging Core was funded by the Wellcome Trust Strategic Award [100574/Z/12/Z].
dc.languageengen
dc.language.isoenen
dc.publisherAmerican Heart Association
dc.subjectadrenal cortexen
dc.subjectprimary aldosteronismen
dc.subjectaldosteroneen
dc.subjectdopamineen
dc.subjectendocrineen
dc.titleNEFM (Neurofilament Medium) Polypeptide, a Marker for Zona Glomerulosa Cells in Human Adrenal, Inhibits D1R (Dopamine D1 Receptor)-Mediated Secretion of Aldosteroneen
dc.typeArticle
prism.endingPage364
prism.issueIdentifier2en
prism.publicationDate2017en
prism.publicationNameHypertensionen
prism.startingPage357
prism.volume70en
dc.identifier.doi10.17863/CAM.12727
dcterms.dateAccepted2017-05-05en
rioxxterms.versionofrecord10.1161/HYPERTENSIONAHA.117.09231en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-08en
dc.contributor.orcidGurnell, Mark [0000-0001-5745-6832]
dc.identifier.eissn1524-4563
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (100574/Z/12/Z)
pubs.funder-project-idBritish Heart Foundation (FS/14/12/30540)
pubs.funder-project-idBritish Heart Foundation (FS/14/75/31134)
cam.issuedOnline2017-06-05en
rioxxterms.freetoread.startdate2017-12-05


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