Angiotensin II Triggers Expression of the Adrenal Gland Zona Glomerulosa-Specific 3 beta-Hydroxysteroid Dehydrogenase Isoenzyme through De Novo Protein Synthesis of the Orphan Nuclear Receptors NGFIB and NURR1

作者：Ota Takumi; Doi Masao^*; Yamazaki Fumiyoshi; Yarimizu Daisuke; Okada Kazuki; Murai Iori; Hayashi Hida; Kunisue Sumihiro; Nakagawa Yuuki; Okamura Hitoshi

来源：Molecular and Cellular Biology, 2014, 34(20): 3880-3894.

DOI：10.1128/MCB.00852-14

The 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) is an enzyme crucial for steroid synthesis. Two different 3 beta-HSD isoforms exist in humans. Classically, HSD3B2 was considered the principal isoform present in the adrenal. However, we recently showed that the alternative isoform, HSD3B1, is expressed specifically within the adrenal zona glomerulosa (ZG), where aldosterone is produced, raising the question of why this isozyme needs to be expressed in this cell type. Here we show that in both human and mouse, expression of the ZG isoform 3 beta-HSD is rapidly induced upon angiotensin II (AngII) stimulation. AngII is the key peptide hormone regulating the capacity of aldosterone synthesis. Using the human adrenocortical H295R cells as a model system, we show that the ZG isoform HSD3B1 differs from HSD3B2 in the ability to respond to AngII. Mechanistically, the induction of HSD3B1 involves de novo protein synthesis of the nuclear orphan receptors NGFIB and NURR1. The HSD3B1 promoter contains a functional NGFIB/NURR1-responsive element to which these proteins bind in response to AngII. Knockdown of these proteins and overexpression of a dominant negative NGFIB both reduce the AngII responsiveness of HSD3B1. Thus, the AngII-NGFIB/NURR1 pathway controls HSD3B1. Our work reveals HSD3B1 as a new regulatory target of AngII.

• 出版日期2014-10