Innovation of novel therapeutics against hypertension targeting CYP11B2 by RXR activation

• 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
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• 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.

Research Products

• [Journal Article] The reduction of heparan sulphate in the glomerular basement membrane does not augment urinary albumin excretion (2018)
  • Author(s): Satoshi Aoki, Akiko Saito-Hakoda, Takeo Yoshikawa, Kyoko Shimizu, Kiyomi Kisu, Susumu Suzuki, Kiyoshi Takagi, Shuji Mizumoto, Shuhei Yamada, Toin H. van Kuppevelt, Atsushi Yokoyama, Taiji Matsusaka, Hiroshi Sato, Sadayoshi Ito, and Akira Sugawara
  • Journal Title: Nephrology Dialysis Transplantation Volume: 33 Issue: 1 Pages: 26-33
  • DOI: 10.1093/ndt/gfx218
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Suppressive effects of RXR agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion and blood pressure (2017)
  • Author(s): Suzuki Dai、Saito-Hakoda Akiko、Ito Ryo、Shimizu Kyoko、Parvin Rehana、Shimada Hiroki、Noro Erika、Suzuki Susumu、Fujiwara Ikuma、Kagechika Hiroyuki、Rainey William E.、Kure Shigeo、Ito Sadayoshi、Yokoyama Atsushi、Sugawara Akira
  • Journal Title: PLoS One Volume: 12 Issue: 8 Pages: e0181055-e0181055
  • DOI: 10.1371/journal.pone.0181055
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High glucose stimulates expression of aldosterone synthase (CYP11B2) and secretion of aldosterone in human adrenal cells (2017)
  • Author(s): Shimada Hiroki、Kogure Naotaka、Noro Erika、Kudo Masataka、Sugawara Kaori、Sato Ikuko、Shimizu Kyoko、Kobayashi Makoto、Suzuki Dai、Parvin Rehana、Saito-Ito Takako、Uruno Akira、Saito-Hakoda Akiko、Rainey William E.、Ito Sadayoshi、Yokoyama Atsushi、Sugawara Akira
  • Journal Title: FEBS Open Bio Volume: 7 Issue: 9 Pages: 1410-1421
  • DOI: 10.1002/2211-5463.12277
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of NeuroD1 on the negative regulation of Pomc expression by glucocorticoid. (2017)
  • Author(s): Parvin R, Saito-Hakoda A, Shimada H, Shimizu K, Noro E, Iwasaki Y, Fujiwara K, Yokoyama A, Sugawara A.
  • Journal Title: PLoS One. Volume: 12(4) Issue: 4 Pages: e0175435-e0175435
  • DOI: 10.1371/journal.pone.0175435
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of RXR agonists on cell proliferation/apoptosis and ACTH secretion/Pomc expression (2015)
  • Author(s): Saito-Hakoda A, Uruno A, Yokoyama A, Shimizu K, Parvin R, Kudo M, Saito-Ito T, Sato I, Kogure N, Suzuki D, Shimada H, Yoshikawa T, Fujiwara I, Kagechika H, Iwasaki Y, Kure S, Ito S, Sugawara A
  • Journal Title: PLoS One Volume: 10 Issue: 12 Pages: e0141960-e0141960
  • DOI: 10.1371/journal.pone.0141960
  • Peer Reviewed / Open Access
• [Presentation] MEKT1, a novel PPAR-gamma agonist, significantly suppressed Pomc expression/ACTH secretion in AtT20 cells (2018)
  • Author(s): Rehana Parvin, Akiko Saito-Hakoda, Hiroki Shimada, Erika Noro, Susumu Suzuki, Hiroyuki Miyachi Atsushi Yokoyama, Akira Sugawara
  • Organizer: ENDO2018
  • Int'l Joint Research
• [Presentation] Suppressive effects of retinoid X receptor (RXR) agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion, and blood pressure (2016)
  • Author(s): Dai Suzuki, Akiko Saito-Hakoda, Ryo Ito, Kyoko Shimizu, Naotaka Kogure, Hiroyuki Kagechika, Shigeo Kure, Atsushi Yokoyama, Akira Sugawara
  • Organizer: 41th Meeting of the International Aldosterone Conference
  • Place of Presentation: アメリカ合衆国ボストン市
  • Year and Date: 2016-03-30
  • Int'l Joint Research
• [Presentation] Inhibitory effects of retinoid X receptor pan-agonist PA024 on adrenal CYP11B2 expression and aldosterone secretion (2016)
  • Author(s): Dai Suzuki, Akiko Saito-Hakoda, Ryo Ito, Kyoko Shimizu, Naotaka Kogure, Hiroyuki Kagechika, Shigeo Kure, Atsushi Yokoyama, Akira Sugawara
  • Organizer: ENDO 2016
  • Place of Presentation: アメリカ合衆国ボストン市
  • Int'l Joint Research
• [Presentation] Suppressive effects of retinoid X receptor (RXR) agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion, and blood pressure (2016)
  • Author(s): Dai Suzuki, Akiko Saito-Hakoda, Ryo Ito, Kyoko Shimizu, Naotaka Kogure, Hiroyuki Kagechika, Shigeo Kure, Atsushi Yokoyama, Akira Sugawara
  • Organizer: The 9th International Aldosterone Forum in Japan
  • Place of Presentation: 東京（品川グランドホール）
  • Int'l Joint Research
• [Presentation] 種々のレチノイドX受容体アゴニストは、AtT20細胞の増殖・アポトーシス・Pomc発現・ACTH分泌に異なる影響を及ぼす (2015)
  • Author(s): 箱田明子、宇留野晃、清水恭子、レハナ・パービン、横山 敦、吉川雄朗、工藤正孝、影近弘之、岩崎泰正、伊藤貞嘉、菅原 明
  • Organizer: 第88回 日本内分泌学会学術総会
  • Place of Presentation: 東京、ホテルニューオータニ
  • Year and Date: 2015-04-23
• [Presentation] レチノイドX受容体アゴニストPA024が副腎CYP11B2発現・アルドステロン分泌に及ぼす影響の検討 (2015)
  • Author(s): 鈴木 大、箱田明子、清水恭子、レハナ・パービン、宇留野晃、青木 聡、佐藤郁子、島田洋樹、小暮直敬、藤原幾麿、伊藤貞嘉、影近弘之、横山 敦、菅原 明
  • Organizer: 第88回 日本内分泌学会学術総会
  • Place of Presentation: 東京、ホテルニューオータニ
  • Year and Date: 2015-04-23
• [Remarks] 分子内分泌学分野
  • URL: http://www.med.tohoku.ac.jp/org/health/84/index.html
• [Remarks] Molecular Endocrinology
  • URL: http://www.med.tohoku.ac.jp/english/org/health/84/index.html