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ID 34200
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Author
Otani, Hiroyuki
Inagaki, Kenichi
Suzuki, Jiro
Kano, Yoshihiro
Goto, Junko
Makino, Hirofumi
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 candesartanpretreated 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.

Keywords
ENZYME-INHIBITOR THERAPY
CHRONIC HEART-FAILURE
CONVERTING ENZYME
HYPERTENSIVE PATIENTS
PLASMA-ALDOSTERONE
GRANULOSA-CELLS
SYSTEM
SECRETION
NEPHROPATHY
HYPERTROPHY
Note
Published with permission from the copyright holder.
This is a author's copy,as published in Endocrinology , 2008 Vol.149 Issue.6 pp.2816-2825
Publisher URL: http://dx.doi.org/10.1210/en.2007-1476
Direct access to Thomson Web of Science record
Copyright © 2008 by The Endocrine Society
Published Date
2008-06-25
Publication Title
Endocrinology
Volume
volume149
Issue
issue6
Start Page
2816
End Page
2825
Content Type
Journal Article
language
英語
Refereed
True
DOI
Web of Sience KeyUT
Submission Path
metabolic_diseases/1