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Investigation of the role of NFAT5 in the regulation of renal interstitial microenviroment and blood pressure

Research Project

Project/Area Number 21K08280
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53040:Nephrology-related
Research InstitutionKumamoto University

Principal Investigator

Izumi Yuichiro  熊本大学, 病院, 特任准教授 (20736243)

Co-Investigator(Kenkyū-buntansha) 向山 政志  熊本大学, 大学院生命科学研究部(医), 教授 (40270558)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords食塩感受性高血圧 / NFAT5 / 上皮型ナトリウムチャネル / 免疫応答 / 腎尿細管 / 高血圧
Outline of Research at the Start

高血圧は、我が国で有病者が推定4000万人を超える国民病であり、心血管疾患、脳卒中、慢性腎臓病の発症、進展の強いリスク因子である。高血圧患者の半数近くが食塩(Na)摂取により高血圧がさらに悪化する食塩感受性高血圧であるとされる。原因として、Naの過剰摂取が腎臓から尿中へのNa排泄を却って妨げるためであることが挙げられるが、その仕組みについては十分に分かっていない。私たちは最近、腎臓の細胞が正常に機能するために重要なNFAT5と呼ばれる分子をマウスで欠損させたところ、食塩感受性高血圧を発症することを見出した。このマウスを詳細に解析することにより、食塩感受性高血圧の発症の仕組みを明らかにする。

Outline of Final Research Achievements

Blood pressure and water and electrolyte metabolism of drug-inducible and renal tubular cell-specific NFAT5 (nuclear activated T-cells 5) KO mice were examined by telemetry method and measurement of urine and blood parameters. The effects of high-salt diet and sodium channel inhibitor on the blood pressure and water and electrolyte metabolism were examined.
The results indicated that the KO mice exhibit salt-sensitive hypertension which is accompanied by the over expression of epithelium sodium channel (ENaC). The activation of immune responses and excessive interstitial osmolality caused by the accumulation of sodium in the renal medulla were observed. In contrast, the interstitial urea level was significantly decreased. We hypothesize that the deficit of NFAT5 in renal tubular cells induces a change of interstitial microenvironment followed by the activation of immune responses, resulting in salt-sensitive hypertension.

Academic Significance and Societal Importance of the Research Achievements

本研究は、ゲノム関連解析で示唆されているヒトの血圧高値と血清ナトリウム濃度高値へのNFAT5の関連を、尿細管細胞特異的NFAT5欠損(KO)マウスを用いて実証したものである。本研究により、正常な水・電解質代謝に必須の腎臓の尿細管細胞において、NFAT5の機能異常が食塩感受性高血圧を呈し、さらにヒトの食塩感受性高血圧の原因と一つとされる上皮型ナトリウム(Na)チャネル(ENaC)を介した尿中Na再吸収亢進と腎組織内の免疫応答の異常を合併することが明らかになった。NFAT5 KOマウスのさらに詳細な解析を進めることで、食塩感受性高血圧の発症・進展機序の解明とその治療法の開発が大いに期待できる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (39 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (3 results) Journal Article (18 results) (of which Int'l Joint Research: 9 results,  Peer Reviewed: 15 results,  Open Access: 11 results) Presentation (18 results) (of which Int'l Joint Research: 6 results,  Invited: 2 results)

  • [Int'l Joint Research] Universitat Pompeu Fabra/Barcelona Biomedical Research Park(スペイン)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Universitat Pompeu Fabra/Barcelona Biomedical Research Park(スペイン)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] Universitat Pompeu Fabra(スペイン)

    • Related Report
      2021 Research-status Report
  • [Journal Article] Tubular Endogenous Erythropoietin Protects Renal Function against Ischemic Reperfusion Injury2024

    • Author(s)
      Yasuoka Yukiko、Izumi Yuichiro、Fukuyama Takashi、Oshima Tomomi、Yamazaki Taiga、Uematsu Takayuki、Kobayashi Noritada、Nanami Masayoshi、Shimada Yoshitaka、Nagaba Yasushi、Mukoyama Masashi、Sands Jeff M.、Takahashi Noriko、Kawahara Katsumasa、Nonoguchi Hiroshi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 25 Issue: 2 Pages: 1223-1223

    • DOI

      10.3390/ijms25021223

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characterization of gene expression in the kidney of renal tubular cell-specific NFAT5 knockout mice2024

    • Author(s)
      Ono Makoto、Izumi Yuichiro、Maruyama Kosuke、Yasuoka Yukiko、Hiramatsu Akiko、Aramburu Jose、L?pez-Rodr?guez Cristina、Nonoguchi Hiroshi、Kakizoe Yutaka、Adachi Masataka、Kuwabara Takashige、Mukoyama Masashi
    • Journal Title

      American Journal of Physiology-Renal Physiology

      Volume: 326 Issue: 3 Pages: F394-F410

    • DOI

      10.1152/ajprenal.00233.2023

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A Serine Protease Inhibitor, Camostat Mesilate, Suppresses Urinary Plasmin Activity and Alleviates Hypertension and Podocyte Injury in Dahl Salt-Sensitive Rats2023

    • Author(s)
      Iwata Yasunobu、Deng Qinyuan、Kakizoe Yutaka、Nakagawa Terumasa、Miyasato Yoshikazu、Nakagawa Miyuki、Nishiguchi Kayo、Nagayoshi Yu、Narita Yuki、Izumi Yuichiro、Kuwabara Takashige、Adachi Masataka、Mukoyama Masashi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 21 Pages: 15743-15743

    • DOI

      10.3390/ijms242115743

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Suppression of Indoxyl Sulfate Accumulation Reduces Renal Fibrosis in Sulfotransferase 1a1-Deficient Mice2023

    • Author(s)
      Hou Huixian、Horikawa Mai、Narita Yuki、Jono Hirofumi、Kakizoe Yutaka、Izumi Yuichiro、Kuwabara Takashige、Mukoyama Masashi、Saito Hideyuki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 14 Pages: 11329-11329

    • DOI

      10.3390/ijms241411329

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Progress in the Detection of Erythropoietin in Blood, Urine, and Tissue2023

    • Author(s)
      Yasuoka Yukiko、Izumi Yuichiro、Sands Jeff M.、Kawahara Katsumasa、Nonoguchi Hiroshi
    • Journal Title

      Molecules

      Volume: 28 Issue: 11 Pages: 4446-4446

    • DOI

      10.3390/molecules28114446

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A case of chyluria with nephrotic-range proteinuria caused by lymphatic malformation, leading to a diagnosis of Klippel-Trenaunay syndrome2022

    • Author(s)
      Izumi Yuichiro、Date Ryosuke、Mizumoto Teruhiko、Nakagawa Terumasa、Kakizoe Yutaka、Adachi Masataka、Kuwabara Takashige、Mukoyama Masashi
    • Journal Title

      CEN Case Reports

      Volume: 12 Issue: 2 Pages: 205-209

    • DOI

      10.1007/s13730-022-00747-6

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Camostat mesilate, a serine protease inhibitor, exerts aquaretic effects and decreases urinary exosomal AQP2 levels2022

    • Author(s)
      Kakizoe Yutaka、Nakagawa Terumasa、Iwata Yasunobu、Deng Qinyuan、Adachi Masataka、Miyasato Yoshikazu、Nakagawa Miyuki、Nagayoshi Yu、Nishiguchi Kayo、Narita Yuki、Izumi Yuichiro、Kuwabara Takashige、Tomita Kimio、Kitamura Kenichiro、Mukoyama Masashi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 150 Issue: 4 Pages: 204-210

    • DOI

      10.1016/j.jphs.2022.09.003

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The serine protease plasmin plays detrimental roles in epithelial sodium channel activation and podocyte injury in Dahl salt-sensitive rats2022

    • Author(s)
      Deng Qinyuan、Kakizoe Yutaka、Iwata Yasunobu、Nakagawa Terumasa、Miyasato Yoshikazu、Nakagawa Miyuki、Nishiguchi Kayo、Nagayoshi Yu、Adachi Masataka、Narita Yuki、Izumi Yuichiro、Kuwabara Takashige、Tsuda Yuko、Mukoyama Masashi
    • Journal Title

      Hypertension Research

      Volume: 46 Issue: 1 Pages: 50-62

    • DOI

      10.1038/s41440-022-01064-2

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] A Novel VCP modulator KUS121 exerts renoprotective effects in ischemia-reperfusion injury with retaining ATP and restoring ERAD-processing capacity.2022

    • Author(s)
      Hata Yusuke、Date Ryosuke、Fujimoto Daisuke、Ikeda Hanako Ohashi、Umemoto Shuro、Kanki Tomoko、Nishiguchi Yoshihiko、Mizumoto Teruhiko、Hayata Manabu、Kakizoe Yutaka、Izumi Yuichiro、Kakizuka Akira、Mukoyama Masashi、Kuwabara Takashige
    • Journal Title

      American Journal of Physiology-Renal Physiology

      Volume: - Issue: 5 Pages: F577-F586

    • DOI

      10.1152/ajprenal.00392.2021

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] サルコペニア・フレイルと代謝性アシドーシス2022

    • Author(s)
      泉裕一郎,向山政志
    • Journal Title

      腎臓内科

      Volume: 16 Pages: 46-52

    • Related Report
      2022 Research-status Report
  • [Journal Article] Effects of Roxadustat on Erythropoietin Production in the Rat Body2022

    • Author(s)
      Yasuoka Yukiko,Izumi Yuichiro,Fukuyama Takashi,Omiya Haruki,Pham Truyen D.,Inoue Hideki,Oshima Tomomi,Yamazaki Taiga,Uematsu Takayuki,Kobayashi Noritada,Shimada Yoshitaka,Nagaba Yasushi,Yamashita Tetsuro,Mukoyama Masashi,Sato Yuichi,Wall Susan M.,Sands Jeff M.,Takahashi Noriko,Kawahara Katsumasa,Nonoguchi Hiroshi
    • Journal Title

      Molecules

      Volume: 27 Issue: 3 Pages: 1119-1119

    • DOI

      10.3390/molecules27031119

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Osteocrin, a bone-derived humoral factor, exerts a renoprotective role in ischemia-reperfusion injury in mice2021

    • Author(s)
      Nishiguchi Yoshihiko、Hata Yusuke、Date Ryosuke、Fujimoto Daisuke、Umemoto Shuro、Kanki Tomoko、Yokoi Hideki、Mori Keita P、Handa Takaya、Watanabe-Takano Haruko、Kanai Yugo、Yasoda Akihiro、Izumi Yuichiro、Kakizoe Yutaka、Mochizuki Naoki、Mukoyama Masashi、Kuwabara Takashige
    • Journal Title

      Nephrology Dialysis Transplantation

      Volume: 37 Issue: 3 Pages: 444-453

    • DOI

      10.1093/ndt/gfab286

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Salt-Sensitive Hypertension of the Renal Tubular Cell-Specific NFAT5 (Nuclear Factor of Activated T-Cells 5) Knockout Mice2021

    • Author(s)
      Hiramatsu Akiko、Izumi Yuichiro、Eguchi Koji、Matsuo Naomi、Deng Qinyuan、Inoue Hideki、Nakayama Yushi、Nonoguchi Hiroshi、Aramburu Jose、Lopez-Rodriguez Cristina、Kakizoe Yutaka、Adachi Masataka、Kuwabara Takashige、Kim-Mitsuyama Shokei、Mukoyama Masashi
    • Journal Title

      Hypertension

      Volume: 78 Issue: 5 Pages: 1335-1346

    • DOI

      10.1161/hypertensionaha.121.17435

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Effects of Angiotensin II on Erythropoietin Production in the Kidney and Liver2021

    • Author(s)
      Yasuoka Yukiko、Izumi Yuichiro、Fukuyama Takashi、Inoue Hideki、Oshima Tomomi、Yamazaki Taiga、Uematsu Takayuki、Kobayashi Noritada、Shimada Yoshitaka、Nagaba Yasushi、Mukoyama Masashi、Sato Yuichi、Sands Jeff M、Kawahara Katsumasa、Nonoguchi Hiroshi
    • Journal Title

      Molecules

      Volume: 26 Issue: 17 Pages: 5399-5399

    • DOI

      10.3390/molecules26175399

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A serine protease inhibitor camostat mesilate prevents podocyte apoptosis and attenuates podocyte injury in metabolic syndrome model rats2021

    • Author(s)
      Mizumoto Teruhiko、Kakizoe Yutaka、Nakagawa Terumasa、Iwata Yasunobu、Miyasato Yoshikazu、Uchimura Kohei、Adachi Masataka、Deng Qinyuan、Hayata Manabu、Morinaga Jun、Miyoshi Taku、Izumi Yuichiro、Kuwabara Takashige、Sakai Yoshiki、Tomita Kimio、Kitamura Kenichiro、Mukoyama Masashi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 146 Issue: 4 Pages: 192-199

    • DOI

      10.1016/j.jphs.2021.04.003

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulation of Rhcg, an ammonia transporter, by aldosterone in the kidney.2021

    • Author(s)
      Eguchi K, Izumi Y, Yasuoka Y, Nakagawa T, Ono M, Maruyama K, Matsuo N, Hiramatsu A, Inoue H, Nakayama Y, Nonoguchi H, Lee HW, Weiner ID, Kakizoe Y, Kuwabara T, Mukoyama M.
    • Journal Title

      J Endocrinol.

      Volume: in press Issue: 2 Pages: 95-112

    • DOI

      10.1530/joe-20-0267

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] 酸塩基平衡とその異常2021

    • Author(s)
      泉裕一郎
    • Journal Title

      看護技術

      Volume: 67 Pages: 1249-1252

    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Journal Article] 尿細管におけるK+の動態2021

    • Author(s)
      泉裕一郎
    • Journal Title

      腎と透析

      Volume: 90 Pages: 701-706

    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] 浸透圧変化~もう一つの水・ナトリウム代謝調節因子~2023

    • Author(s)
      泉裕一郎、向山政志
    • Organizer
      日本腎臓学会学術総会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Possible involvement of renal tubular NFAT5 in aging-associated renal phenotypes and dysfunction2023

    • Author(s)
      Maruyama K, Izumi Y, Ono M, Kakizoe Y, Kuwabara T, Mukoyama M.
    • Organizer
      米国腎臓学会 Kidney Week 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 腎尿細管細胞内NFAT5の加齢に伴う腎機能障害および食塩感受性高血圧への関与の可能性2023

    • Author(s)
      丸山功祐、泉裕一郎、小野真、柿添豊、桒原孝成、向山政志
    • Organizer
      日本高血圧学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 腎尿細管細胞におけるNFAT5の加齢に伴う腎機能障害への関与の可能性2023

    • Author(s)
      丸山功祐、泉裕一郎、小野真、柿添豊、桒原孝成、向山政志
    • Organizer
      日本腎臓学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] ENaC依存性の血圧と体液量調節における浸透圧応答転写因子NFAT5の意義2022

    • Author(s)
      泉裕一郎,平松晶子,江口剛人,松尾尚美,鄧欽元,野々口博史,柿添豊,安達政隆,桒原孝成,光山勝慶,向山政志
    • Organizer
      日本腎臓学会学術総会
    • Related Report
      2022 Research-status Report
  • [Presentation] 食塩感受性高血圧の病態~塩とNFAT5の関わりから~2022

    • Author(s)
      泉裕一郎,向山政志
    • Organizer
      日本腎臓学会西部学術大会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] Involvement of renal tubular NFAT5 in the regulation of blood pressure and body fluid volume2022

    • Author(s)
      Izumi Y, Hiramatsu A, Eguchi K, Matsuo N, Deng Q, Inoue H, Nakayama Y, Nonoguchi H, Aramburu J, Lopez-Rodriguez C, Kakizoe Y, Adachi M, Kuwabara T, Kim-Mitsuyama S, Mukoyama M
    • Organizer
      International Society of Hypertension
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Possible involvement of renal tubular NFAT5 in aging-associated renal dysfunction2022

    • Author(s)
      Maruyama K, Izumi Y, Ono M, Kakizoe Y, Morinaga J, Kuwabara T, mukoyama M
    • Organizer
      International Symposium on Cardiovascular Endocrinology and Metabolism
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] 浸透圧応答転写因子NFAT5のENaCに依存した血圧と体液調節における意義の検討2022

    • Author(s)
      泉裕一郎,平松晶子,江口剛人,松尾尚美,鄧欽元,野々口博史,柿添豊,安達政隆,桒原孝成,光山勝慶,向山政志
    • Organizer
      臨床高血圧フォーラム
    • Related Report
      2022 Research-status Report
  • [Presentation] 腎尿細管細胞内NFAT5の食塩感受性高血圧における意義の検討2021

    • Author(s)
      平松 晶子, 泉 裕一郎, 江口 剛人, 松尾 尚美, 小野 真, 丸山 功祐, 中山 祐史, 井上 秀樹, 柿添 豊, 桑原 孝成, 向山 政志
    • Organizer
      日本高血圧学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 腎集合尿細管間在細胞のアルドステロンによる尿中酸排泄機序の検討2021

    • Author(s)
      泉 裕一郎, 江口 剛人, 小野 真, 平松 晶子, 井上 秀樹, 中山 裕史, 柿添 豊, 桑原 孝成, 向山 政志
    • Organizer
      日本高血圧学会臨床高血圧フォーラム
    • Related Report
      2021 Research-status Report
  • [Presentation] 尿細管細胞内NFAT5による腎間質線維化抑制の機序の検討2021

    • Author(s)
      小野 真, 泉 裕一郎, 松尾 尚美, 江口 剛人, 平松 晶子, 丸山 功祐, 中山 裕史, 井上 秀樹, 森永 潤, 柿添 豊, 桑原 孝成, 向山 政志
    • Organizer
      日本腎臓学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 尿中酸排泄に対するユビキチンープロテアソーム系の意義の検討2021

    • Author(s)
      丸山 功祐, 泉 裕一郎, 小野 真, 平松 晶子, 柿添 豊, 桑原 孝成, 向山 政志
    • Organizer
      日本腎臓学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 腎尿細管細胞内NFAT5の塩分感受性高血圧への関与の検討2021

    • Author(s)
      平松 晶子, 泉 裕一郎, 江口 剛人, 松尾 尚美, 小野 真, 丸山 功祐, 中山 裕史, 井上 秀樹, 柿添 豊, 桑原 孝成, 向山 政志
    • Organizer
      日本心血管内分泌代謝学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] Involvement of renal tubular NFAT5, an osmoresponsive transcription factor, in urine concentration and sodium reabsorption2021

    • Author(s)
      Akiko Hiramatsu, Yuichiro Izumi, Koji Eguchi, Naomi Matsuo, Makoto Ono, Yushi Nakayama, Hideki Inoue, Yutaka Kakizoe, Takashige Kuwabara, and Masashi Mukoyama
    • Organizer
      International Society of Hypertension
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Urinary ammonium excretion by aldosterone through the regulation of Rh C glycoprotein in the intercalated cells of the renal collecting duct2021

    • Author(s)
      Yuichiro Izumi, Koji Eguchi, Makoto Ono, Akiko Hiramatsu, Hideki Inoue, Yushi Nakayama, Hiroshi Nonoguchi, Yutaka Kakizoe, Takashige Kuwabara, and Masashi Mukoyama
    • Organizer
      International Society of Hypertension
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Regulation of sodium excretion and blood pressure by the nuclear factor of activated T cells 5, NFAT5, in renal tubular cells2021

    • Author(s)
      Akiko Hiramatsu, Yuichiro Izumi, Yutaka Kakizoe, Masataka Adachi, Hiroshi Nonoguchi, Takashige Kuwabara, and Masashi Mukoyama
    • Organizer
      American Society of Nephrology Kidney Week
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] 腎集合尿細管における新規転写因子の意義と食塩感受性高血圧の機序に関する研究2021

    • Author(s)
      泉裕一郎、平松晶子、江口剛人、松尾尚美、鄧欽元、柿添豊、安達政隆、桒原孝成、光山勝慶、向山政志
    • Organizer
      高血圧関連疾患モデル学会学術総会
    • Related Report
      2021 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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