RRC ID 49245
Author Suzuki D, Saito-Hakoda A, Ito R, Shimizu K, Parvin R, Shimada H, Noro E, Suzuki S, Fujiwara I, Kagechika H, Rainey WE, Kure S, Ito S, Yokoyama A, Sugawara A.
Title Suppressive effects of RXR agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion and blood pressure.
Journal PLoS One
Abstract The effects of retinoids on adrenal aldosterone synthase gene (CYP11B2) expression and aldosterone secretion are still unknown. We therefore examined the effects of nuclear retinoid X receptor (RXR) pan-agonist PA024 on CYP11B2 expression, aldosterone secretion and blood pressure, to elucidate its potential as a novel anti-hypertensive drug. We demonstrated that PA024 significantly suppressed angiotensin II (Ang II)-induced CYP11B2 mRNA expression, promoter activity and aldosterone secretion in human adrenocortical H295R cells. Human CYP11B2 promoter functional analyses using its deletion and point mutants indicated that the suppression of CYP11B2 promoter activity by PA024 was in the region from -1521 (full length) to -106 including the NBRE-1 and the Ad5 elements, and the Ad5 element may be mainly involved in the PA024-mediated suppression. PA024 also significantly suppressed the Ang II-induced mRNA expression of transcription factors NURR1 and NGFIB that bind to and activate the Ad5 element. NURR1 overexpression demonstrated that the decrease of NURR1 expression may contribute to the PA024-mediated suppression of CYP11B2 transcription. PA024 also suppressed the Ang II-induced mRNA expression of StAR, HSD3β2 and CYP21A2, a steroidogenic enzyme group involved in aldosterone biosynthesis. Additionally, the PA024-mediated CYP11B2 transcription suppression was shown to be exerted via RXRα. Moreover, the combination of PPARγ agonist pioglitazone and PA024 caused synergistic suppressive effects on CYP11B2 mRNA expression. Finally, PA024 treatment significantly lowered both the systolic and diastolic blood pressure in Tsukuba hypertensive mice (hRN8-12 x hAG2-5). Thus, RXR pan-agonist PA024 may be a candidate anti-hypertensive drugs that acts via the suppression of aldosterone synthesis and secretion.
Volume 12(8)
Pages e0181055
Published 2017-8-11
DOI 10.1371/journal.pone.0181055
PII PONE-D-16-42602
PMID 28800627
PMC PMC5553648
MeSH 2-Naphthylamine / analogs & derivatives* 2-Naphthylamine / pharmacology Adrenal Cortex / drug effects Adrenal Cortex / metabolism* Aldosterone / metabolism* Animals Apoptosis / drug effects Blood Pressure / drug effects* Body Weight / drug effects Calcium / metabolism Cell Line, Tumor Cell Proliferation / drug effects Cytochrome P-450 CYP11B2 / genetics Cytochrome P-450 CYP11B2 / metabolism* Heart Rate / drug effects Humans Hydrocortisone / metabolism Ions Mice, Transgenic Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism Pioglitazone Point Mutation / genetics Promoter Regions, Genetic Pyrimidines / pharmacology* RNA, Messenger / genetics RNA, Messenger / metabolism Retinoid X Receptors / antagonists & inhibitors* Retinoid X Receptors / metabolism Sequence Deletion / genetics Steroids / biosynthesis Thiazolidinediones / pharmacology
IF 2.74
Times Cited 3
Mice RBRC02432