title: Enhancement of aldosterone-induced catecholamine production by bone morphogenetic protein-4 through activating Rho and SAPK/JNK pathway in adrenomedullar cells.
abstract: Here we investigated the effects of mineralocorticoid in the regulation of catecholamine biosynthesis using rat pheochromocytoma PC12 cells. Expression of mineralocorticoid receptor (MR) was confirmed in undifferentiated PC12 cells. Aldosterone stimulated dopamine production by PC12 cells without any increase in cAMP activity. Aldosterone-induced dopamine accumulation was enhanced in accordance with the increase in the rate-limiting enzyme tyrosine hydroxylase (TH). Blocking MR with eplerenone suppressed aldosterone-induced increases of TH mRNA and dopamine production. A glucocorticoid receptor (GR) antagonist, RU-486, attenuated dexamethasone- but not aldosterone-induced TH expression. Cycloheximide reduced both aldosterone- and dexamethasone-induced TH mRNA. A SAPK/JNK inhibitor, SP600125, suppressed aldosterone-induced TH mRNA expression; however, the aldosterone-induced TH expression was not affected by inhibition of ERK1/2, p38-MAPK, Rho-kinase, PI 3-kinase, and PKC. It was of note that cotreatment with eplerenone and SP600125 restored aldosterone-induced TH mRNA expression to basal levels. To investigate the involvement of bone morphogenetic protein (BMP) actions in aldosterone-induced catecholamine production, we examined the effects of BMP-4 and BMP-7, which are expressed in the adrenal medulla, on catecholamine biosynthesis. BMP-4 preferentially enhanced aldosterone-induced TH mRNA and dopamine production, although BMP-4 alone did not affect TH expression. The BMP-4 enhancement of aldosterone-induced TH expression was not observed in cells treated with eplerenone. BMP-4 did not affect MR expression of PC12 cells; however, it did enhance aldosterone-induced SAPK/JNK phosphorylation. Inhibition of SAPK/JNK or Rho suppressed BMP-4 enhancement of aldosterone-induced TH expression. Collectively, our findings demonstrate that aldosterone stimulates catecholamine biosynthesis in adrenomedullar cells via MR through genomic action and partly through nongenomic action by Rho-SAPK/JNK signaling, the latter of which is facilitated by BMP-4. A functional link between MR actions and endogenous BMP may be involved in the catecholamine production.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama City, 700-8558, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Goto
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.forename: Misuzu
authors.initials: M
authors.lastname: Yamashita
authors.forename: Jiro
authors.initials: J
authors.lastname: Suzuki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Otani
authors.forename: Hiroko
authors.initials: H
authors.lastname: Takahashi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Yukari
authors.initials: Y
authors.lastname: Mimura
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000313:Adrenal Medulla / Q000187:drug effects* / Q000378:metabolism; D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D016716:PC12 Cells; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002395:Catecholamines; D018160:Receptors, Cytoplasmic and Nuclear; D000450:Aldosterone; D014446:Tyrosine 3-Monooxygenase; D048055:Mitogen-Activated Protein Kinase 8; D020741:rho GTP-Binding Proteins