Role of Rac1-mediated activation of mineralocorticoid receptor in heart failure

• Project/Area Number: 26860546
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: The University of Tokyo
• Principal Investigator: Ayuzawa Nobuhiro 東京大学, 先端科学技術研究センター, 特任研究員 (50459517)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 高血圧 / 心不全 / 低分子量G蛋白質 / 鉱質コルチコイド受容体 / 低分子G蛋白質 / Rac1 / ミネラロコルチコイド受容体 / 酸化ストレス / ノックアウトマウス / トランスジェニックマウス

Outline of Final Research Achievements

Activation of mineralocortcoid receptor (MR) is closely involved in the development of heart failure, and MR blockade is now an important strategy in the treatment of heart failure. However, the mechanism of MR activation in heart failure is still unclear. Recently, a small GTPase Rac1 was identified as a novel factor that is involved in MR activation in kidney diseases. In the present study, we demonstrated that Rac1 mediates MR activation in the heart using a mice model of pressure overload-induced heart failure, and that the activation of Rac1-MR pathway leads to cardiac dysfunction through indcution of oxidative stress.

Research Products

• [Journal Article] Aldosterone is essential for angiotensin II-induced upregulation of pendrin. (2018)
  • Author(s): Hirohama D, Ayuzawa N, Ueda K, Nishimoto M, Kawarazaki W, Watanabe A, Shimosawa T, Marumo T, Shibata S, Fujita T
  • Journal Title: J Am Soc Nephrol Volume: 29 Issue: 1 Pages: 57-68
  • DOI: 10.1681/asn.2017030243
  • Peer Reviewed / Open Access
• [Journal Article] Rac1-Mediated Activation of Mineralocorticoid Receptor in Pressure Overload-Induced Cardiac Injury (2016)
  • Author(s): Nobuhiro Ayuzawa, Miki Nagase, Kohei Ueda, Mitsuhiro Nishimoto, Wakako Kawarazaki, Takeshi Marumo, Atsu Aiba, Takayuki Sakurai, Takayuki Shindo, Toshiro Fujita
  • Journal Title: Hypertension Volume: 67 Issue: 1 Pages: 99-106
  • DOI: 10.1161/hypertensionaha.115.06054
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Mineralocorticoid receptor in renal intercalated cells mediates pendrin regulation by renin-angiotensin-aldosterone system to maintain fluid homeostasis (2018)
  • Author(s): Nobuhiro Ayuzawa, Mitsuhiro Nishimoto, Daigoro Hirohama, Kohei Ueda, Wakako Kawarazaki, Tastuo Shimosawa, Takeshi Marumo, Toshiro Fujita
  • Organizer: Gordon Research Seminar, Angiotensin
  • Int'l Joint Research
• [Presentation] Mineralocorticoid receptor in renal intercalated cells mediates pendrin regulation by renin-angiotensin-aldosterone system to maintain fluid homeostasis (2018)
  • Author(s): Nobuhiro Ayuzawa, Mitsuhiro Nishimoto, Daigoro Hirohama, Kohei Ueda, Wakako Kawarazaki, Tastuo Shimosawa, Takeshi Marumo, Toshiro Fujita
  • Organizer: Gordon Research Conference, Angiotensin
  • Int'l Joint Research
• [Presentation] 腎間在細胞ミネラロコルチコイド受容体欠損マウスを用いたPendrin制御機構の解析 (2017)
  • Author(s): 鮎澤信宏、上田浩平、広浜大五郎、西本光宏、河原崎和歌子、渡邉篤史、丸茂丈史、藤田敏郎
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] Activation of Rac1-MR pathway in heart failure (2015)
  • Author(s): Nobuhiro Ayuzawa
  • Organizer: 8th International Aldosterone Forum in Japan
  • Place of Presentation: Tokyo (Japan)
  • Year and Date: 2015-05-30
  • Int'l Joint Research
• [Presentation] Activation of Rac1-MR pathway in heart failure (2015)
  • Author(s): Nobuhiro Ayuzawa
  • Organizer: The 8th International Aldosterone Forum in Japan
  • Place of Presentation: THE GRAND HALL（品川）、東京都
  • Year and Date: 2015-05-30