title: Involvement of bone morphogenetic protein-6 in differential regulation of aldosterone production by angiotensin II and potassium in human adrenocortical cells.
abstract: Aldosterone production is modified by several growth factors that reside in the adrenal. We have recently reported the existence of a bone morphogenetic protein (BMP) system in human adrenocortical cells, in which BMP-6 augments aldosterone synthesis. Here, we investigated functional roles of BMP-6, focusing on the differential regulation of aldosterone synthesis induced by angiotensin (Ang) II and potassium (K). In human adrenocortical H295R cells, BMP-6 augmented Ang II-induced CYP11B2 transcription and mRNA and aldosterone production but had no effect on K-induced aldosterone production. Inhibition of endogenous BMP-6 action by neutralizing antibodies impaired aldosterone production induced by Ang II but not that induced by K. Blockage of ligand-receptor binding using extracellular domain (ECD) of BMP type I receptors revealed that ECDs to activin receptor-like kinase (ALK)-2 and ALK-3 significantly reduced the aldosterone production induced by Ang II. None of the type I-receptor ECDs tested had any effect on K-induced aldosterone levels. Overexpression of a dominant negative-activin type II receptor construct selectively decreased Ang II-induced aldosterone production without having any effect on K-induced aldosterone production. BMP type II receptor-dominant negative had no effect on aldosterone induced by either Ang II or K. These results infer that BMP-6 acts through ALK-2, ALK-3, and activin type II receptor receptors in adrenocortical cells. BMP-6 pretreatment extends the induction of ERK1/2 phosphorylation by Ang II and treatment with ECDs to ALK-2 and ALK-3 impaired Ang II-induced ERK phosphorylation. The specific inhibitor of ERK activation, U0126, suppressed the activation of CYP11B2 transcription induced by BMP-6 without affecting Smad phosphorylation and Tlx2-Luc activity. Collectively, the endogenous BMP-6 system plays critical roles in aldosterone production between Ang II and K through ERK signaling pathway.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City 700-8558, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.forename: Jiro
authors.initials: J
authors.lastname: Suzuki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kano
authors.forename: Masaya
authors.initials: M
authors.lastname: Takeda
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Otani
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: D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000494:pharmacology*; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002460:Cell Line; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D011188:Potassium / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology
chemical_list: C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D048049:Extracellular Signal-Regulated MAP Kinases; D011188:Potassium