Analysis of pendrin regulation using mice with deletion of mineralocorticoid receptor in renal intercalated cells

• Project/Area Number: 18K15969
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• 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): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 高血圧 / 腎臓 / ミネラロコルチコイド受容体 / アンジオテンシンII / アルドステロン / Pendrin / NCC / 食塩感受性 / ミネラロコルチコイド / 腎

Outline of Final Research Achievements

Pendrin, expressed in β-intercalated cells (ICs) in renal cortical collecting ducts, mediates NaCl reabsorption, and contributes to the regulation of fluid balance and blood pressure. We showed that, during volume depletion, angiotensin II causes pendrin activation via mineralocorticoid receptor (MR) in ICs, and that this pathway maintains fluid volume and blood pressure. We also showed that, during primary aldosterone excess, hypokalemic alkalosis caused by activation of the MR-ENaC pathway in principal cells directly induces pendrin activation independently of MR in ICs, resultantly causing salt-sensitive hypertension. Furthermore, we show that these pathways act as complementary pathways for NCC, a thiazide diuretic target.

Academic Significance and Societal Importance of the Research Achievements

高血圧は世界中で多く見られ、心血管・腎臓病の重大なリスクである。複数の降圧薬が開発されてきたが、治療抵抗例も少なくない。例えば、腎遠位曲尿細管のNCCを阻害しNaCl再吸収を抑えて降圧作用を示すサイアザイド利尿薬は第一選択薬であるが、一部症例ではレニン・アンジオテンシン・アルドステロン系（RAAS）の活性化や低K血症性アルカローシスなどを呈して治療抵抗性になることがある。
本研究成果により、サイアザイド利尿薬抵抗性の高血圧の治療においてMR拮抗薬が有用な治療戦略となることが示唆された。また、今回見出されたPendrinの制御の仕組みのさらなる解明により、新たな治療標的の発見も期待される。

Research Products

• [Journal Article] Two Mineralocorticoid Receptor-Mediated Mechanisms of Pendrin Activation in Distal Nephrons. (2020)
  • Author(s): Ayuzawa N, Nishimoto M, Ueda K, Hirohama D, Kawarazaki W, Shimosawa T, Marumo T, Fujita T.
  • Journal Title: J Am Soc Nephrol. Volume: 31 Issue: 4 Pages: 748-764
  • DOI: 10.1681/asn.2019080804
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Two different mechanism of pendrin regulation by mineralocorticoid receptor in distal nephron (2019)
  • Author(s): Nobuhiro Ayuzawa, Mitsuhiro Nishimoto, Daigoro Hirohama, Wakako Kawarazaki, Takeshi Marumo, Toshiro Fujita
  • Organizer: The International Symposium of Aldosterone and Related Substance in Hypertension 2019
  • Int'l Joint Research
• [Presentation] ミネラロコルチコイド過剰による食塩感受性高血圧におけるPendrin活性化機構 (2019)
  • Author(s): 鮎澤信宏、広浜大五郎、西本光宏、河原崎和歌子、丸茂丈史、藤田敏郎
  • Organizer: 第62回 日本腎臓学会学術総会
• [Presentation] Two distinct regulations of pendrin by mineralocorticoid receptor in distal nephron (2019)
  • Author(s): Nobuhiro Ayuzawa
  • Organizer: The 44th International Aldosterone Conference
  • Int'l Joint Research
• [Presentation] Mineralocorticoid receptor in renal intercalated cells mediates RAAS-driven pendrin regulation to maintain fluid homeostasis (2018)
  • Author(s): Nobuhiro Ayuzawa
  • Organizer: 第61回 日本腎臓学会学術総会
• [Remarks] 尿への食塩排泄量を調節するPendrinにより 治療に抵抗性の高血圧が起こる仕組みを解明
  • URL: https://www.rcast.u-tokyo.ac.jp/ja/news/release/20200208.html