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

2022 Fiscal Year Final Research Report

• 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
• Keywords: 腎臓 / 慢性腎臓病 / 脂質代謝物 / AMPK / エネルギー代謝

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.

Free Research Field

腎臓内科学

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。