title: Role of D2 dopamine receptor in adrenal cortical cell proliferation and aldosterone-producing adenoma tumorigenesis.
abstract: Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia are the two characteristic types of primary aldosteronism. Dysregulation of adrenal cortical cell proliferation contributes to both diseases. We previously demonstrated that APA expressed less dopamine D2 receptor than the respective non-tumor tissue and might contribute to the overproduction of aldosterone. As activation of D2 receptor inhibits the proliferation of various cells, downregulation of D2 receptor in APA may play a role in the tumorigenesis of APA. In this study, we demonstrate that D2 receptor plays a role in angiotensin II (AII)-stimulated adrenal cortical cell proliferation. The D2 receptor agonist, bromocriptine, inhibited AII-stimulated cell proliferation in primary cultures of the normal human adrenal cortex and APA through attenuating AII-induced phosphorylation of PK-stimulated cyclin D1 protein expression and cell proliferation. D2 receptor also inhibited AII-induced ERK1/2 phosphorylation. Our results demonstrate that, in addition to inhibiting aldosterone synthesis/production, D2 receptor exerts an anti-proliferative effect in adrenal cortical and APA cells by attenuating PKCμ and ERK phosphorylation. The lower level of expression of D2 receptor in APA may augment cell proliferation and plays a crucial role in the tumorigenesis of APA. Our novel finding suggests a new therapeutic target for primary aldosteronism.
authors.affiliation: Nephrology Division, Department of Internal Medicine, Room 1419, National Taiwan University Hospital, Clinical Research Building, 7 Chung-Sun South Road, Taipei 100, Taiwan Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Chang
authors.forename: Chao-Yuan
authors.initials: CY
authors.lastname: Huang
authors.forename: Shao-Yu
authors.initials: SY
authors.lastname: Yang
authors.forename: Vin-Cent
authors.initials: VC
authors.lastname: Wu
authors.forename: Tzong-Shinn
authors.initials: TS
authors.lastname: Chu
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Chen
authors.forename: Bor-Shen
authors.initials: BS
authors.lastname: Hsieh
authors.forename: Kwan-Dun
authors.initials: KD
authors.lastname: Wu
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000473:pathology*; D000302:Adrenal Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D000310:Adrenal Gland Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D000450:Aldosterone / Q000096:biosynthesis*; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*
chemical_list: C581293:DRD2 protein, human; D065127:Dopamine D2 Receptor Antagonists; D005419:Flavonoids; D007527:Isoenzymes; D044140:Receptor, Angiotensin, Type 1; D017448:Receptors, Dopamine D2; D019938:Cyclin D1; D000450:Aldosterone; C089212:protein kinase D; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: aldosterone-producing adenoma; cell proliferation; dopamine receptor; protein kinase C