title: Angiotensin II receptor blockers differentially affect CYP11B2 expression in human adrenal H295R cells.
abstract: We generated a stable H295R cell line expressing aldosterone synthase gene (CYP11B2) promoter/luciferase chimeric reporter construct that is highly sensitive to angiotensin II (AII) and potassium, and defined AII receptor blocker (ARB) effects. In the presence of AII, all ARBs suppressed AII-induced CYP11B2 transcription. However, telmisartan alone increased CYP11B2 transcription in the absence of AII. Telmisartan dose-dependently increased CYP11B2 transcription/mRNA expression and aldosterone secretion. Experiments using CYP11B2 promoter mutants indicated that the Ad5 element was responsible. Among transcription factors involved in the element, telmisartan significantly induced NGFIB/NURR1 expression. KN-93, a CaMK inhibitor, abrogated the telmisartan-mediated increase of CYP11B2 transcription/mRNA expression and NURR1 mRNA expression, but not NGFIB mRNA expression. NURR1 over-expression significantly augmented the telmisartan-mediated CYP11B2 transcription, while high-dose olmesartan did not affect it. Taken together, telmisartan may stimulate CYP11B2 transcription via NGFIB and the CaMK-mediated induction of NURR1 that activates the Ad5 element, independent of AII type 1 receptor.
authors: Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors: Ken
authors: K
authors: Matsuda
authors: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors: Akira
authors: A
authors: Uruno
authors: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors: Naotaka
authors: N
authors: Kogure
authors: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors: Kaori
authors: K
authors: Sugawara
authors: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors: Hiroki
authors: H
authors: Shimada
authors: Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors: Masahiro
authors: M
authors: Nezu
authors: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors: Takako
authors: T
authors: Saito-Ito
authors: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors: Yuko
authors: Y
authors: Iki
authors: Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors: Masataka
authors: M
authors: Kudo
authors: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors: Kyoko
authors: K
authors: Shimizu
authors: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors: Ikuko
authors: I
authors: Sato
authors: Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors: Takeo
authors: T
authors: Yoshikawa
authors: Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors: Fumitoshi
authors: F
authors: Satoh
authors: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors: Ryo
authors: R
authors: Ito
authors: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors: Atsushi
authors: A
authors: Yokoyama
authors: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109-5622, USA.
authors: William E
authors: WE
authors: Rainey
authors: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors: Akiko
authors: A
authors: Saito-Hakoda
authors: Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors: Sadayoshi
authors: S
authors: Ito
authors: Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. Electronic address: akiras2i@med.tohoku.ac.jp.
authors: Akira
authors: A
authors: Sugawara
mesh_terms: D000311:Adrenal Glands; D000450:Aldosterone / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011945:Receptors, Angiotensin / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology; D014158:Transcription, Genetic; D000096926:Benzenesulfonamides
chemical_list: D000450:Aldosterone; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001565:Benzoates; D001596:Benzylamines; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019405:Cytochrome P-450 CYP11B2; D007093:Imidazoles; D008156:Luciferases; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047428:Protein Kinase Inhibitors; D011945:Receptors, Angiotensin; D013449:Sulfonamides; D000077333:Telmisartan; D013777:Tetrazoles; C539821:NR4A1 protein, human; C072105:KN 93; D000096926:Benzenesulfonamides; C437965:olmesartan
keywords: ARB; Aldosterone; CYP11B2