Innovation of novel therapeutics against hypertension targeting CYP11B2 by RXR activation

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09420
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Tohoku University
• Principal Investigator: Hakoda Akiko 東北大学, 医学系研究科, 大学院非常勤講師 (70509398)
• Co-Investigator(Kenkyū-buntansha): 菅原 明 東北大学, 医学系研究科, 教授 (90270834)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: アルドステロン / 高血圧 / レチノイド / RXR / CYP11B2

Outline of Final Research Achievements

PA024 dose-dependently suppressed AII-induced CYP11B2 mRNA expression/promoter activity. Additionally, high-dose PA024 significantly decreased aldosterone secretion. The suppression of CYP11B2 promoter activity by PA024 was observed in the deletion mutants analyses using the region from -1521 (full length) to -135 including NBRE-1, Ad4, and Ad5 elements. PA024 also suppressed mRNA expression of transcription factors Nurr1 and NGFIB in a dose-dependent manner. Since PA024-mediated suppression of CYP11B2 promoter activity was rescued by Nurr1 overexpression, decrease of Nurr1 expression may contribute to the suppression. PA024 also inhibited mRNA expression of StAR, HSD3β2, and CYP21A2. Therefore, PA024-mediated suppression of these enzymes may also be involved in the inhibition of aldosterone synthesis. Furthermore, PA024 significantly lowered systemic blood pressure in THM.

Free Research Field

内分泌代謝学