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Exploration of gluco- and mineralocorticoid-dependent sodium transporter system involved in salt sensitive hypertension

Research Project

Project/Area Number 16K15494
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Endocrinology
Research InstitutionThe University of Tokyo

Principal Investigator

Fujita Toshiro  東京大学, 先端科学技術研究センター, 特任研究員 (10114125)

Co-Investigator(Kenkyū-buntansha) 鮎澤 信宏  東京大学, 先端科学技術研究センター, 特任研究員 (50459517)
丸茂 丈史  東京大学, 医学部附属病院, その他 (70265817)
Project Period (FY) 2016-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords食塩感受性高血圧 / ミネラルコルチコイド / 遠位尿細管 / 鉱質コルチコイド受容体 / ペンドリン / 高血圧 / 酸塩基異常 / 内科
Outline of Final Research Achievements

Pendrin is expressed in intercalated cells of the renal tubules and plays a pivotal role in maintenance of body fluid and blood pressure. The present study revealed the essential role of aldosterone-mineralocorticoid receptor (MR) pathway in the activation of pendrin by angiotensin II using adrenalectomy model and MR knockout mice, paving the way to the development of new therapy against salt-sensitive hypertension.
Apparent mineralocorticoid excess (APE) is caused by mutations in the HSD11B2 gene, which lead to hypertension. To delineate the role of the kidney, we generated mice with kidney-specific deletion of HSD11B2. These mice developed hypertension, along with activation of epithelial sodium channel-Na+-Cl- cotransporter activation. Mineralocorticoid receptor antagonist decreased blood pressure of the knockout mice. These results suggest the importance of 11beta HSD2 expressed in the kidney in MR activation and development of hypertension in APE syndrome.

Report

(3 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • Research Products

    (26 results)

All 2018 2017 2016

All Journal Article (7 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 7 results,  Open Access: 3 results) Presentation (19 results) (of which Int'l Joint Research: 4 results,  Invited: 1 results)

  • [Journal Article] Aldosterone is essential for angiotensin II-induced upregulation of pendrin2018

    • 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

    • DOI

      10.1681/asn.2017030243

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aberrant DNA methylation of pregnane X receptor underlies metabolic gene alterations in the diabetic kidney2018

    • Author(s)
      Uchida K, Tanaka Y, Ichikawa H, Watanabe M, Mitani S, Morita K, Fujii H, Ishikawa M, Yoshino G, Okinaga H, Nagae G, Aburatani H, Ikeda Y, Susa T, Tamamori-Adachi M, Fukusato T, Uozaki H, Okazaki T, Iizuka M
    • Journal Title

      American Journal of Physiology-Renal Physiology

      Volume: 314 Issue: 4 Pages: F551-F560

    • DOI

      10.1152/ajprenal.00390.2017

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stromal Interaction Molecule 1 modulates blood pressure via NO production in vascular endothelial cells2018

    • Author(s)
      Nishimoto M, Mizuno R, Fujita T, Isshiki M
    • Journal Title

      Hypertens Res in press

      Volume: -

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Renal dysfunction induced by kidney-specific gene deletion of Hsd11b2 as a primary cause of salt-dependent hypertension2017

    • Author(s)
      Kohei Ueda, Mitsuhiro Nishimoto, Daigoro Hirohama, Nobuhiro Ayuzawa, Wakako Kawarazaki, Atsushi Watanabe, Tatsuo Shimosawa, Johannes Loffing, Ming-Zhi Zhang, Takeshi Marumo, and Toshiro Fujita
    • Journal Title

      Hypertension

      Volume: -

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Hypokalemia and Pendrin Induction by Aldosterone2017

    • Author(s)
      Xu N, Hirohama D, Ishizawa K, Chang WX, Shimosawa T, Fujita T, Uchida S, Shibata S
    • Journal Title

      Hypertension

      Volume: 69 Issue: 5 Pages: 855

    • DOI

      10.1161/hypertensionaha.116.08519

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 32016

    • Author(s)
      Kenichi Ishizawa, Ning Xu, Johannes Loffing, Richard P. Lifton, Toshiro Fujita, Shunya Uchida, Shigeru Shibata.
    • Journal Title

      Biochem Biophys Res Commun. 2016 Nov

      Volume: 480 Issue: 4 Pages: 745

    • DOI

      10.1016/j.bbrc.2016.10.127

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis.2016

    • Author(s)
      Currie G, Taylor AH, Fujita T, Ohtsu H, Lindhardt M, Rossing P, Boesby L, Edwards NC, Ferro CJ, Townend JN, van den Meiracker AH, Saklayen MG, Oveisi S, Jardine AG, Delles C, Preiss DJ, Mark PB.
    • Journal Title

      BMC Nephrol.

      Volume: 17 Issue: 1 Pages: 127-140

    • DOI

      10.1186/s12882-016-0337-0

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Aldosterone is essential for angiotensin II-induced upregulation of pendrin2018

    • Author(s)
      Daigoro Hirohama, Nobuhiro Ayuzawa, Kohei Ueda, Mitsuhiro Nishimoto, Wakako Kawarazaki, Tatsuo Shimosawa, Takeshi Marumo, Shigeru Shibata, Toshiro Fujita
    • Organizer
      International Aldosterone Conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Mineralocorticoid receptor in renal intercalated cells mediates pendrin regulation by renin-angiotensin-aldosterone system to maintain fluid homeostasis2018

    • Author(s)
      Nobuhiro Ayuzawa, Mitsuhiro Nishimoto, Daigoro Hirohama, Kohei Ueda, Wakako Kawarazaki, Tastuo Shimosawa, Takeshi Marumo, Toshiro Fujita
    • Organizer
      Gordon Research Conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Aldosterone is essential for angiotensin II-induced upregulation of pendrin2017

    • Author(s)
      Daigoro Hirohama, Nobuhiro Ayuzawa, Kohei Ueda, Mitsuhiro Nishimoto,Wakako Kawarazaki, Atsushi Watanabe, Tatsuo Shimosawa, Takeshi Marumo, Shigeru Shibata, Toshiro Fujita
    • Organizer
      American Society of Nephrology Kidney Week 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Systemic effect of renal 11beta-HSD2 deficiency on blood pressure regulation2017

    • Author(s)
      Kohei Ueda, Mitsuhiro Nishimoto, Daigoro Hirohama, Nobuhiro Ayuzawa, Wakako Kawarazaki, Atsushi Watanabe, Tatsuo Shimosawa, Johannes Loffing, Ming-Zhi Zhang, Takeshi Marumo, Toshiro Fujita
    • Organizer
      AHA Council on Hypertension American Society of Hypertension Joint Scientific Sessions
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 食塩感受性高血圧の内分泌学的および腎生理学的検討2017

    • Author(s)
      西本光宏、上田浩平、河原崎和歌子、水野理介、森典子、渡邉篤史、広浜大五郎、鮎澤信宏、大庭成喜、丸茂丈史、藤田敏郎
    • Organizer
      第90回日本内分泌学会学術総会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 高血圧とエピジェネティクス~妊娠時低栄養による食塩感受性高血圧発症の中枢神経機序の解明~2017

    • Author(s)
      森典子、西本光宏、藤田敏郎
    • Organizer
      第40回日本高血圧学会総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 腎臓特異的な11beta HSD2活性低下による高血圧発症機序の解析2017

    • Author(s)
      上田浩平、西本光宏、広浜大五郎、鮎澤信宏、河原崎和歌子、渡邉篤史、下澤達雄、丸茂丈史、藤田敏郎
    • Organizer
      第40回日本高血圧学会総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 加齢と食塩感受性高血圧~抗加齢因子Klothoの発現低下はRhoA活性化による血管収縮を惹起する~2017

    • 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、上田浩平、渡邉篤史、丸茂丈史、藤田敏郎
    • Organizer
      第40回日本高血圧学会総会
    • Related Report
      2017 Annual Research Report
  • [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
    • Related Report
      2017 Annual Research Report
  • [Presentation] 抗加齢因子Klothoの発現低下は腎mTORC1の活性化を介して食塩感受性高血圧を惹起する2017

    • Author(s)
      河原崎和歌子、西本光宏、鮎澤信宏、広浜大五郎、上田浩平、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
    • Related Report
      2017 Annual Research Report
  • [Presentation] PendrinとNCC発現調節におけるアンジオテンシンIIとアルドステロンの異なる役割2017

    • Author(s)
      広浜 大五郎、 柴田 茂、上田 浩平、鮎澤 信宏、西本 光宏、河原崎 和歌子、渡邉 篤史、下澤 達雄、丸茂 丈史、藤田 敏郎
    • Organizer
      第60回 日本腎臓学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 特異的DNAメチル化signatureを用いた糖尿病性腎症の尿細管障害診断2017

    • Author(s)
      丸茂丈史、下澤達雄、河原崎和歌子、西本光宏、鮎澤信宏、広浜大五郎、上田浩平、渡邉篤史、星野純一、乳原善文、藤田敏郎
    • Organizer
      第60回 日本腎臓学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 糖尿病性腎症でエピゲノム異常をきたす核内受容体PXRは腎糖新生を調整する2017

    • Author(s)
      渡邉篤史 丸茂丈史 河原崎和歌子 西本光宏 鮎澤信宏 広浜大五郎 上田浩平 熊谷裕生 藤田敏郎
    • Organizer
      第60回 日本腎臓学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 腎pendrinの発現機構と 血圧調節における役割の解明2017

    • Author(s)
      広浜 大五郎、鮎澤 信宏、上田 浩平、西本 光宏、河原崎 和歌子、渡邉 篤史、下澤 達雄、丸茂 丈史、柴田 茂、藤田 敏郎
    • Organizer
      第21回心血管内分泌代謝学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 腎臓エピゲノム情能に基づく生活習慣病に対する治療戦略2016

    • Author(s)
      丸茂丈史, 藤田敏郎
    • Organizer
      第39回日本高血圧学会総会
    • Place of Presentation
      仙台
    • Year and Date
      2016-09-30
    • Related Report
      2016 Research-status Report
  • [Presentation] 間在細胞EGFP標識マウスを用いた間在細胞分取・解析法の確立2016

    • 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59回 日本腎臓学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2016-06-19
    • Related Report
      2016 Research-status Report
  • [Presentation] 抗加齢因子Klotho発現低下に伴う食塩感受性高血圧発症機序の解明2016

    • Author(s)
      河原崎和歌子, 丸茂丈史, 西本光宏, 鮎澤信宏, 広浜大五郎, 上田浩平, 渡邉篤史, 藤田敏郎
    • Organizer
      第59回 日本腎臓学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2016-06-19
    • Related Report
      2016 Research-status Report
  • [Presentation] PendrinとNCC発現調節におけるアンジオテンシンIIとアルドステロンの異なる役割2016

    • Author(s)
      広浜大五郎, 柴田茂, 上田浩平, 鮎澤信宏, 西本光宏, 河原崎和歌子, 渡邉篤史, 丸茂丈史, 藤田敏郎
    • Organizer
      第59回 日本腎臓学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2016-06-19
    • Related Report
      2016 Research-status Report
  • [Presentation] 糖尿病性腎症で核内受容体PXRはエピジェネティクス異常をきたし線維化因子RGC32を増加させる2016

    • Author(s)
      渡邉篤史, 丸茂丈史, 河原崎和歌子, 西本光宏, 鮎澤信宏, 広浜大五郎, 上田浩平, 熊谷裕生, 藤田敏郎
    • Organizer
      第59回 日本腎臓学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2016-06-17
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2019-03-29  

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