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Elucidation of the Pathogenesis and Repair Mechanism of Acute Kidney Injury by a New Approach from Redox Dysregulation

Research Project

Project/Area Number 18K08203
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53040:Nephrology-related
Research InstitutionUniversity of Fukui

Principal Investigator

Kasuno Kenji  福井大学, 学術研究院医学系部門, 准教授 (60455243)

Co-Investigator(Kenkyū-buntansha) 岩野 正之  福井大学, 学術研究院医学系部門, 教授 (20275324)
木村 秀樹  福井大学, 学術研究院医学系部門(附属病院部), 准教授 (20283187)
高橋 直生  福井大学, 学術研究院医学系部門(附属病院部), 助教 (30377460)
三上 大輔  福井大学, 学術研究院医学系部門(附属病院部), 助教 (90464586)
松本 英樹  福井大学, 学術研究院医学系部門, 准教授 (40142377)
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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords急性腎障害 / 酸化ストレス / レドックス / チオレドキシン / G2/M細胞周期停止 / バイオマーカー / 尿中チオレドキシン / AKI-to-CKD transition / 慢性腎臓病 / 細胞周期
Outline of Final Research Achievements

The relationship between the redox regulator thioredoxin (TXN) and AKI-to-CKD transition was investigated. Depending on the severity of AKI, TXN increased in the urine and decreased in the tubular cells. In accordance with the decrease of TXN, phosphorylation of redox-sensitive G2/M cell cycle regulator Cdc25C was increased and the localization was changed from nucleus to cytoplasm in wild-type mice with severe AKI. Subsequent AKI-to-CKD transition including G2/M arrest, interstitial fibrosis, and elevation of serum creatinine were observed in these mice. In contrast, these findings of AKI-to-CKD transition were suppressed in TXN transgenic mice. In humans, high urinary TXN levels at the AKI onset were associated with subsequent chronic maintenance dialysis dependency. These results suggest that TXN is involved in G2/M cell cycle arrest in AKI-to-CKD transition. Urinary TXN is useful for the G2/M arrest biomarker in AKI and also a companion diagnostic for redox-modulating therapeutics.

Academic Significance and Societal Importance of the Research Achievements

AKIやCKDは病因が特定されていないため、病因を標的とした個別化医療の展開が困難で、現在は病因によらず腎機能によって画一的に診断されている。一方で腎臓のレドックス調節不全を標的としてBardoxolone methylを始めとするレドックス調節薬が開発されている。病因に基づいた治療薬の登場により、分子メカニズムに基づいて適切な治療法選択に役立つバイオマーカーが求められている。
本研究成果は、尿中TXNが腎臓のレドックス調節異常を検出できることを示唆している。さらなる研究により、尿中TXNがレドックス調節薬に反応する患者を特定するコンパニオン診断薬として腎臓病の個別化医療に貢献すると考えられる。

Report

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

    (9 results)

All 2020 2019 2018

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (4 results) Patent(Industrial Property Rights) (4 results) (of which Overseas: 2 results)

  • [Journal Article] Analytical and Clinical validation of rapid chemiluminescence enzyme immunoassay for urinary thioredoxin, an oxidative stress-dependent early biomarker of acute kidney injury2020

    • Author(s)
      Seiji Yokoi, Kenji Kasuno, Kazuhisa Nishimori, Sho Nishikawa, Yudai Nishikawa, Sayu Morita, Mamiko Kobayashi, Sachiko Fukushima, Daisuke Mikami, Naoki Takahashi, Yumiko Oota, Hideki Kimura, Yoshihiro Soya, Shinsuke Kimata, Kengo Nishimura, Takahiko Ono, Eri Muso, Haruyoshi Yoshida, Junji Yodoi, and Masayuki Iwano
    • Journal Title

      Clinica Chimica Acta

      Volume: 507 Pages: 271-279

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Redox dysregulation after acute renal injury is a novel pathophysiology of AKI-to-CKD transition2020

    • Author(s)
      糟野健司
    • Organizer
      第63回日本腎臓学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] レドックス制御破綻を介したG2/M細胞周期停止による新たなAKI-to-CKD transitionのメカニズムと診断・治療への応用について2020

    • Author(s)
      糟野健司
    • Organizer
      第50回日本腎臓学会西部学術大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Urinar y thioredoxin 1 as a G2/M cell cycle arrest marker of acute kidney injury2019

    • Author(s)
      糟野健司
    • Organizer
      第62回日本腎臓学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Intracellular thioredoxin depletion triggers tubular epithelial cell cycle arrest at G2/M after acute kidney injury2018

    • Author(s)
      糟野健司
    • Organizer
      第61回日本腎臓学会学術総会
    • Related Report
      2018 Research-status Report
  • [Patent(Industrial Property Rights)] 腎障害の予防剤または治療剤2020

    • Inventor(s)
      糟野健司
    • Industrial Property Rights Holder
      糟野健司
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2019 Research-status Report
    • Overseas
  • [Patent(Industrial Property Rights)] 腎障害の予防剤または治療剤2019

    • Inventor(s)
      糟野健司
    • Industrial Property Rights Holder
      糟野健司
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-114970
    • Filing Date
      2019
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] 尿中チオレドキシンの測定により、急性腎障害からの回復の予測や慢性移行の可能性を推定する技術2019

    • Inventor(s)
      糟野健司
    • Industrial Property Rights Holder
      糟野健司
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2018 Research-status Report
    • Overseas
  • [Patent(Industrial Property Rights)] 尿中チオレドキシンの測定により、急性腎障害からの回復の予測や慢性移行の可能性を推定する技術2018

    • Inventor(s)
      糟野健司
    • Industrial Property Rights Holder
      糟野健司
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-066043
    • Filing Date
      2018
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2023-12-25  

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