Elucidation of the pathogenesis of chronic kidney disease and development of new therapeutic agents using renal tissue lipidomics

• Project/Area Number: 21K20710
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0801:Pharmaceutical sciences and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Takahashi Naohiro 東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (20907737)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 腎臓 / 慢性腎臓病 / 脂質代謝物 / AMPK / エネルギー代謝 / 脂肪酸 / リピドミクス / 多価不飽和脂肪酸

Outline of Research at the Start

我々はメタボローム解析の中でも近年急速に技術進歩が見られたリピドミクスをCKDモデルの腎組織解析に応用し、脂肪酸代謝酵素ALOX15とCKDの関連を明らかにした。脂質メディエーターに対してこれまでにCKDマウスや患者の血清でリピドミクスは行われてきたが、CKD腎組織のリピドミクスは我々の報告で初めて行われた。我々は線虫由来のω3系脂肪酸合成酵素fat-1 TgマウスがCKDに抵抗性であることを確認しており、fat-1の導入で変化したCKD腎臓における脂質メディエーターのプロファイルを網羅的解析で捉えることで、CKDの新規治療標的となるω3系脂肪酸代謝物を提示する。

Outline of Final Research Achievements

We demonstrated that AMPK and ULK1 activities were decreased in the kidneys of CKD mice. However, whether and how ULK1 is involved in the underlying mechanism of CKD exacerbation remains unknown. In this study, we investigated the ULK1 involvement in CKD, using ULK1 knockout mice. The CKD model of Ulk1/ mice exhibited significantly exacerbated renal function and worsening renal fibrosis. In the kidneys of the CKD model of Ulk1/ mice, reduced AMPK and its downstream β-oxidation could be observed, leading to an energy deficit of increased AMP/ATP ratio. In addition, AMPK signaling in the kidney was reduced in control Ulk1/ mice with normal renal function compared to con- trol wild-type mice, suggesting that ULK1 deficiency suppressed AMPK activity in the kidney. This study is the first to present ULK1 as a novel therapeutic tar- get for CKD treatment, which regulates AMPK activity in the kidney.

Academic Significance and Societal Importance of the Research Achievements

本研究では、ULK1蛋白の欠乏がCKDモデルマウスの腎機能の増悪、腎線維化の悪化に繋がることを明らかにした。さらに、ULK1の欠乏はAMPKの活性を抑制し、β酸化の低下から腎組織内のエネルギー不全につながることを示した。今回の発見は、CKDの進行と腎組織内のエネルギー恒常性維持におけるULK1の新しい役割を明らかにするものである。このことはULK1がCKD治療の新規ターゲットとなる可能性を示唆しており、意義深いものと考えられた。

Research Products

• [Journal Article] Absence of ULK1 decreases AMPK activity in the kidney, leading to chronic kidney disease progression (2023)
  • Author(s): Tomoki Yanagi, Hiroaki Kikuchi, Koichiro Susa, Naohiro Takahashi, Naohiro Takahashi, Hiroki Bamba, Takefumi Suzuki, Yuta Nakano, Tamami Fujiki, Yutaro Mori, Fumiaki Ando, Shintaro Mandai, Takayasu Mori, Koh Takeuchi, Shinya Honda, Satoru Torii, Shigeomi Shimizu, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara
  • Journal Title: Genes to Cells Volume: 28 Issue: 1 Pages: 5-14
  • DOI: 10.1111/gtc.12989
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of Alox15 improves kidney dysfunction and inhibits fibrosis by increased PGD2 in the kidney (2021)
  • Author(s): Takahashi Naohiro、Kikuchi Hiroaki、Usui Ayaka、Furusho Taisuke、Fujimaru Takuya、Fujiki Tamami、Yanagi Tomoki、Matsuura Yoshiaki、Asano Kenichi、Yamamoto Kouhei、Ando Fumiaki、Susa Koichiro、Mandai Shintaro、Mori Takayasu、Rai Tatemitsu、Uchida Shinichi、Arita Makoto、Sohara Eisei
  • Journal Title: Clinical and Experimental Nephrology Volume: 25 Issue: 5 Pages: 445-455
  • DOI: 10.1007/s10157-021-02021-y
  • Peer Reviewed / Open Access