YM750, an ACAT Inhibitor, Acts on Adrenocortical Cells to Inhibit Aldosterone Secretion Due to Depolarization

Hiroki Shimada, Shuko Hata, Yuto Yamazaki, Yuri Otsubo, Ikuko Sato, Kazue Ise, Atsushi Yokoyama, Takashi Suzuki, Hironobu Sasano, Akira Sugawara, Yasuhiro Nakamura

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1 Citation (Scopus)

Abstract

Primary aldosteronism (PA) is considered the most common form of secondary hypertension, which is associated with excessive aldosterone secretion in the adrenal cortex. The cause of excessive aldosterone secretion is the induction of aldosterone synthase gene (CYP11B2) expression by depolarization of adrenocortical cells. In this study, we found that YM750, an Acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, acts on adrenocortical cells to suppress CYP11B2 gene expression and aldosterone secretion. YM750 inhibited the induction of CYP11B2 gene expression by KCl stimulation, but not by angiotensin II and forskolin stimulation. Interestingly, YM750 did not inhibit KCl-stimulated depolarization via an increase in intracellular calcium ion concentration. Moreover, ACAT1 expression was relatively abundant in the zona glomerulosa (ZG) including these CYP11B2-positive cells. Thus, YM750 suppresses CYP11B2 gene expression by suppressing intracellular signaling activated by depolarization. In addition, ACAT1 was suggested to play an important role in steroidogenesis in the ZG. YM750 suppresses CYP11B2 gene expression and aldosterone secretion in the adrenal cortex, suggesting that it may be a potential therapeutic agent for PA.

Original languageEnglish
Article number12803
JournalInternational Journal of Molecular Sciences
Volume23
Issue number21
DOIs
Publication statusPublished - 2022 Nov

Keywords

  • ACAT1
  • aldosterone
  • CYP11B2
  • immunohistochemistry
  • NURR1
  • YM750
  • ZG

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