Suppressive effects of RXR agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion and blood pressure.

Dai Suzuki,Erika Noro,Atsushi Yokoyama,Akira Sugawara,Susumu Suzuki,Ikuma Fujiwara,William E Rainey,Rehana Parvin,Kyoko Shimizu,Sadayoshi Ito,Hiroki Shimada,Ryo Ito,Akiko Saito-Hakoda,Shigeo Kure,Hiroyuki Kagechika,Hiroyoshi Ariga

doi:10.1371/journal.pone.0181055

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.

Highlights

Hypertension has long been recognized as a major risk factor for cardiovascular disease, stroke, and chronic kidney disease [1]
We examined the effects of retinoid X receptor (RXR) pan-agonist PA024 on H295R cells proliferation using a WST-8 assay after incubation with various concentrations of PA024 for 48 h
Pan et al reported that pioglitazone promoted CYP11B2 expression but inhibited aldosterone production in angiotensin II (Ang II)-treated human adrenocortical HAC15 cells, a clone of NCI H295R cells [31]

Summary

Introduction

Hypertension has long been recognized as a major risk factor for cardiovascular disease, stroke, and chronic kidney disease [1]. In 2010, the number of patients with hypertension was reported to be 31.1% of the world’s adult population (an estimated 1.39 billion people) [2], and the prevalence has been reported to be increasing, especially in low- and middle-income countries since 2000 [2]. Approximately 20–30% of hypertensive patients are estimated to be ‘‘resistant hypertension” in spite of the concurrent use of more than 3 antihypertensive agents [3]. In order to treat the growing number of patients with ‘‘resistant hypertension,” the development of novel antihypertensive drugs are needed

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