title: Aldosterone breakthrough caused by chronic blockage of angiotensin II type 1 receptors in human adrenocortical cells: possible involvement of bone morphogenetic protein-6 actions.
abstract: Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6, which is expressed in adrenocortical cells, enhances Ang II- but not potassium-induced aldosterone production in human adrenocortical cells. Accordingly, we examined the roles of BMP-6 in aldosterone breakthrough induced by long-term treatment with ARB. Ang II stimulated aldosterone production by adrenocortical cells. This Ang II stimulation was blocked by an ARB, candesartan. Interestingly, the candesartan effects on Ang II-induced aldosterone synthesis and CYP11B2 expression were attenuated in a course of candesartan treatment for 15 d. The impairment of candesartan effects on Ang II-induced aldosterone production was also observed in Ang II- or candesartan-pretreated cells. Levels of Ang II type 1 receptor mRNA were not changed by chronic candesartan treatment. However, BMP-6 enhancement of Ang II-induced ERK1/2 signaling was resistant to candesartan. The BMP-6-induced Smad1, -5, and -8 phosphorylation, and BRE-Luc activity was augmented in the presence of Ang II and candesartan in the chronic phase. Chronic Ang II exposure decreased cellular expression levels of BMP-6 and its receptors activin receptor-like kinase-2 and activin type II receptor mRNAs. Cotreatment with candesartan reversed the inhibitory effects of Ang II on the expression levels of these mRNAs. The breakthrough phenomenon was attenuated by neutralization of endogenous BMP-6 and activin receptor-like kinase-2. Collectively, these data suggest that changes in BMP-6 availability and response may be involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB.
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: Hiroyuki
authors.initials: H
authors.lastname: Otani
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.forename: Jiro
authors.initials: J
authors.lastname: Suzuki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kano
authors.forename: Junko
authors.initials: J
authors.lastname: Goto
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 / Q000502:physiology*; D000450:Aldosterone / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002460:Cell Line; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology; D014162:Transfection
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; C525816:BMP6 protein, human; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000450:Aldosterone; C081643:candesartan