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Elucidation of the Mechanism of Age-Related Salt-Sensitive Hypertension and Novel Therapeutic Strategies

Research Project

Project/Area Number 18K08028
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionThe University of Tokyo

Principal Investigator

Kawarazaki Wakako  東京大学, 先端科学技術研究センター, 特任准教授 (50424594)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords加齢 / 食塩感受性 / 高血圧 / Wnt / Rho / Klotho / 食塩感受性高血圧
Outline of Final Research Achievements

It has been known from epidemiological studies that both the incidence of hypertension and salt sensitivity increase with age, but their mechanisms have been unclear. Using aged mice, we clarified the mechanism by which excessive salt intake in the presence of decreased Klotho in the blood causes activation of the Wnt5a-RhoA system in the vasoconstrictor pathway, resulting in increased vasoconstrictor response and development of hypertension. In addition, we showed that age-related hypertension was significantly suppressed by Klotho supplementation, Wnt inhibitors, and Rho kinase inhibitors. This study provides a novel therapeutic strategy for hypertension in the elderly and emphasizes the importance of salt reduction.

Academic Significance and Societal Importance of the Research Achievements

学術的意義としては、Wnt non-canonical経路が加齢現象や高血圧発症に関わる事、重要な血管収縮物質であるアンジオテンシンⅡ(AngⅡ)による血管収縮にはWnt5aが必要でありWnt5a-RhoA経路の活性化を介して生じ、Klothoにより抑制されることを初めて明らかにした。また、高齢マウスの腎動脈ではAngⅡへの感受性が増大しており、食塩摂取時にWnt-RhoA経路活性化による血管収縮性の増強が腎動脈で生じ、腎血流が低下して高血圧を発症する機序を証明し、Klotho補充にて正常化することを示した。また社会に高齢者高血圧の新規治療法を提示するとともに、減塩の重要性を発信した。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (15 results)

All 2021 2020 2019 2018 Other

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (9 results) (of which Invited: 3 results) Remarks (2 results)

  • [Journal Article] Kidney and epigenetic mechanisms of salt-sensitive hypertension.2021

    • Author(s)
      Kawarazaki W, Fujita T.
    • Journal Title

      Nat Rev Nephrol.

      Volume: 17 Issue: 5 Pages: 350-363

    • DOI

      10.1038/s41581-021-00399-2

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of Rho in Salt-Sensitive Hypertension2021

    • Author(s)
      Kawarazaki Wakako、Fujita Toshiro
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 6 Pages: 2958-2958

    • DOI

      10.3390/ijms22062958

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency2020

    • Author(s)
      Kawarazaki Wakako、Mizuno Risuke、Nishimoto Mitsuhiro、Ayuzawa Nobuhiro、Hirohama Daigoro、Ueda Kohei、Kawakami-Mori Fumiko、Oba Shigeyoshi、Marumo Takeshi、Fujita Toshiro
    • Journal Title

      Journal of Clinical Investigation

      Volume: 130 Pages: 4152-4166

    • DOI

      10.1172/jci134431

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency2020

    • Author(s)
      Kawarazaki W, Mizuno R, Nishimoto M, Ayuzawa N, Hirohama D, Ueda K, Kawakami-Mori F, Oba S, Marumo T and Fujita.
    • Journal Title

      J Clin invest

      Volume: -

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 加齢に伴う高血圧発症機序の解明~食塩の関与~2020

    • Author(s)
      河原崎和歌子
    • Organizer
      Vascular Biology Innovationに関する研究助成第15回研究発表会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 加齢に伴う高血圧発症機序の解明~食塩の関与~2020

    • Author(s)
      河原崎和歌子
    • Organizer
      第15回JJK 腎と高血圧フォーラム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 加齢に伴う高血圧発症機序の解明~食塩の関与~2020

    • Author(s)
      河原崎和歌子
    • Organizer
      CVMW2020血管生物シンポジウム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 加齢に伴う食塩感受性高血圧発症における腎血管性機序の検討2020

    • Author(s)
      河原崎 和歌子, 水野 理介, 西本 光宏, 鮎澤 信宏, 広浜 大五郎, 大庭 成嘉, 丸茂 丈史, 藤田 敏郎.
    • Organizer
      第63回日本腎臓学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 「老化に伴う食塩感受性高血圧発症機序の解明」2019

    • Author(s)
      河原崎和歌子, 水野理介, 西本光宏, 鮎澤信宏, 広浜大五郎, 森典子, 大庭成喜, 丸茂丈史, 藤田敏郎.
    • Organizer
      第62回日本腎臓学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 「加齢に伴う食塩感受性高血圧発症機序の解明」2019

    • Author(s)
      河原崎和歌子, 水野理介, 西本光宏, 鮎澤信宏, 広浜大五郎, 大庭成喜, 丸茂丈史, 藤田敏郎.
    • Organizer
      第42回日本高血圧学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 「加齢に伴う食塩感受性高血圧発症機序の解明」2019

    • Author(s)
      河原崎和歌子, 水野理介, 西本光宏, 鮎澤信宏, 広浜大五郎, 大庭成喜, 丸茂丈史, 藤田敏郎
    • Organizer
      第29回日本循環薬理学会・第55回高血圧関連疾患モデル学会合同学会
    • Related Report
      2019 Research-status Report
  • [Presentation] 加齢に伴う食塩感受性高血圧発症機序の検討2018

    • Author(s)
      河原崎和歌子
    • Organizer
      第61回日本腎臓学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 加齢に伴う食塩感受性高血圧発症におけるKlotho-Wnt-Rho pathwayの関与2018

    • Author(s)
      河原崎和歌子
    • Organizer
      第41回日本高血圧学会総会
    • Related Report
      2018 Research-status Report
  • [Remarks] 高齢者高血圧の発症機序を解明 ~食塩の関与~

    • URL

      https://www.rcast.u-tokyo.ac.jp/ja/news/release/20200630.html

    • Related Report
      2020 Annual Research Report
  • [Remarks] 『Splendid basic Hypertension Research Award』を受賞

    • URL

      https://www.rcast.u-tokyo.ac.jp/ja/news/report/191101.html

    • Related Report
      2019 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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