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Analysis of metabolic alterations in diabetic kidney disease and development of new treatment strategy by amelioration of metabolic alterations

Research Project

Project/Area Number 19K17717
Research Category

Grant-in-Aid for Early-Career Scientists

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

Principal Investigator

Fujii Kentaro  慶應義塾大学, 医学部(信濃町), 助教 (70626390)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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)
Keywords腎虚血 / 糖尿病性腎臓病 / 代謝変容 / アデニル酸代謝 / アミノ酸代謝 / 腎代謝変容 / ロイシン / 急性腎障害 / キサンチンオキシダーゼ阻害薬 / 虚血性腎症 / エネルギー代謝異常 / マスイメージング / キサンチオンキシダーゼ阻害薬 / エネルギー代謝障害
Outline of Research at the Start

本研究では, ストレプトゾトシン(STZ)投与による糖尿病モデルマウスと, 腎動脈に金属製コイルを巻き付けたSTZ投与マウスに対して腎臓マスイメージングとメタボローム解析を行い, 慢性虚血を伴うことでDKDを模倣したマウスの腎臓におけるアデニル酸代謝変容について空間的な解析を行う. さらに, Febuxostat投与に伴う腎臓のアデニル酸代謝変容の改善やpyruvate dehydrogenaseの制御による腎保護効果について検証する.また近位尿細管培養細胞を用いた解析を行い, トランスクリプトーム解析にて, 代謝変容の真の原因となる代謝酵素を明らかにし, 新規腎保護戦略の開発と提言を目指す.

Outline of Final Research Achievements

We successfully visualized the metabolic alteration in different parts of the kidney semi-quantitatively by combining MALDI-IMS and metabolome analyses. Febuxostat, a xanthine oxidase inhibitor, increased ATP by promoting re-synthesis of adenine nucleotides via the salvage pathway, and showed reno-protective effect. Metabolomic analysis of streptozotocin-induced diabetic model mice showed increase of BCAA (isoleucine, leucine, and valine) and significant BCAA accumulation, especially in glomeruli. Progressive renal failure and increased total acetylation of histones H3 and H4 in renal tissues were also observed in leucine-treated STZ mice.

Academic Significance and Societal Importance of the Research Achievements

腎慢性虚血に伴うアデニル酸喪失の回復のためATP投与やミトコンドリア賦活化などの基礎検討が行われてきたが、実臨床の応用には至っていない。本研究では、尿酸降下薬としてすでに上市されているFebuxostatが、腎アデニル酸を回復させ腎保護効果を示すことが示された。本研究により、腎臓における慢性虚血によるアデニル酸代謝変容の病態メカニズムと, 糖尿病性腎臓病の病態プロセスにおける新たな代謝変容が示され、アデニル酸代謝やアミノ酸代謝の変容への治療介入による、新規腎保護戦略が提案された。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (7 results)

All 2020 2019 Other

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (5 results) (of which Int'l Joint Research: 2 results) Remarks (1 results)

  • [Journal Article] Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides.2019

    • Author(s)
      Fujii K, Kubo A, Miyashita K, Sato M, Hagiwara A, Inoue H, Ryuzaki M, Tamaki M, Hishiki T, Hayakawa N, Kabe Y, Itoh H, Suematsu M.
    • Journal Title

      JCI insight

      Volume: 4 Issue: 22 Pages: 124816-124816

    • DOI

      10.1172/jci.insight.124816

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Febuxostat promoted re-synthesis of adenine nucleotides via the HPRT1-dependent purine salvage pathway and exerted reno-protective effect2020

    • Author(s)
      Kentaro Fujii, Kazutoshi Miyashita, Akiko Kubo, Masaaki Sato, Aika Hagiwara, Hiroyuki Inoue, Masaki Ryuzaki, Makoto Suematsu, Hiroshi Itoh
    • Organizer
      第63回日本腎臓学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 高濃度アデノシンによるA2b受容体活性化を介した腎血流維持による腎保護効果の検討2019

    • Author(s)
      藤井健太郎, 宮下和季, 久保亜紀子, 佐藤正明, 萩原あいか, 井上博之, 竜崎正毅, 末松誠, 伊藤裕
    • Organizer
      第92回 日本内分泌学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] DISTRIBUTION OF ADENOSINE IN THE KIDNEY DETERMINES LOCAL VASCULAR TONE VIA A2b ACTIVATION AND AFFECTS RENO2019

    • Author(s)
      Kentaro Fujii, Kazutoshi Miyashita, Akiko Kubo, Masaaki Sato, Aika Hagiwara, Hiroyuki Inoue, Masaki Ryuzaki, Makoto Suematsu, Hiroshi Itoh
    • Organizer
      56th ERA-EDTA
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] A2b受容体活性化を介した高濃度アデノシンの腎血流維持による腎保護効果の解析2019

    • Author(s)
      藤井健太郎, 宮下和季, 久保亜紀子, 佐藤正明, 萩原あいか, 井上博之, 竜崎正毅, 末松誠, 木内謙一郎, 伊藤裕
    • Organizer
      第61回 日本腎臓学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Protective role of adenosine in the renal corticomedullary boundary zone against acute ischemia - findings from mass imaging analysis2019

    • Author(s)
      Kazutoshi Miyashita, Kentaro Fujii, Akiko Kubo, Masaaki Sato, Aika Hagiwara, Hiroyuki Inoue, Masaki Ryuzaki, Makoto Suematsu, Hiroshi Itoh
    • Organizer
      Hypertension Jeju 2019 in Conjunction with the 51st Scientific Meeting of the Korean Society of Hypertension
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Remarks] 尿酸降下薬による腎保護メカニズムの解明~質量分析イメージングによる腎代謝解析~

    • URL

      http://kompas.hosp.keio.ac.jp/sp/contents/medical_info/science/202003.html

    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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