Pathophysiological significance of renal energy metabolism in diabetic kidney disease

• Project/Area Number: 21K16166
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Yokohama City University
• Principal Investigator: AZUSHIMA Kengo 横浜市立大学, 医学部, 助教 (00760381)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 糖尿病性腎臓病 / 脂肪酸酸化 / レニン・アンジオテンシン系 / エネルギー代謝 / アシルカルニチン / レニン-アンジオテンシン系

Outline of Research at the Start

近年，腎臓におけるエネルギー代謝障害，特に脂肪酸酸化障害が慢性腎臓病の進展を促進することが明らかになり，新規の治療標的として注目されている．本研究では，研究代表者が新たに開発した理想的なヒト糖尿病性腎臓病モデルマウスおよびメタボローム解析による網羅的解析手法を駆使して，糖尿病性腎臓病における腎エネルギー代謝の役割の詳細な検討，および腎エネルギー代謝に着目した新規治療法の探索を行う．また，腎生検により得られたヒト腎組織を用いて，ヒト糖尿病性腎臓病における腎エネルギー代謝の意義の検討も行い，糖尿病性腎臓病の新たな病態生理解明および新規治療法開発を目指す．

Outline of Final Research Achievements

Dysfunction of renal energy metabolism has recently been reported to be associated with chronic kidney disease progression. In this study, we intended to investigate the pathophysiological role of renal energy metabolism in the development of diabetic kidney disease (DKD), using progressive DKD model mice. Compared to their wild-type control mice, levels of even-chain acylcarnitines, which reflect fatty acid oxidation (FAO) function, in the progressive DKD mice were broadly reduced along with significant alteration in FAO-related genes expression. These changes were restored by ARB treatment. The results of this study indicate that FAO dysfunction plays a certain role in the development of DKD and could become a new target to treat DKD.

Academic Significance and Societal Importance of the Research Achievements

近年，腎臓のエネルギー代謝障害が，慢性腎臓病の進展に関わることが報告されているが，これまで糖尿病性腎臓病（DKD）における腎エネルギー代謝に関する報告は少なかった．本研究成果は，腎臓におけるエネルギー代謝の中でも，脂肪酸酸化（FAO）機能障害がDKD進展に関連していることを示唆しており，エネルギー代謝，特にFAOへの介入は，DKDに対する新しい治療候補となり得ることを明らかにした．

Research Products

• [Int'l Joint Research] Duke-NUS Medical School(シンガポール)
• [Int'l Joint Research] Duke-NUS Medical School(シンガポール)
• [Journal Article] Deficiency of the kidney tubular angiotensin II type1 receptor?associated protein ATRAP exacerbates streptozotocin-induced diabetic glomerular injury via reducing protective macrophage polarization (2022)
  • Author(s): Haruhara Kotaro、Suzuki Toru、Wakui Hiromichi、Azushima Kengo、Kurotaki Daisuke、Kawase Wataru、Uneda Kazushi、Kobayashi Ryu、Ohki Kohji、Kinguchi Sho、Yamaji Takahiro、Kato Ikuma、Ohashi Kenichi、Yamashita Akio、Tamura Tomohiko、Tsuboi Nobuo、Yokoo Takashi、Tamura Kouichi
  • Journal Title: Kidney International Volume: 101 Issue: 5 Pages: 912-928
  • DOI: 10.1016/j.kint.2022.01.031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Angiotensin II type-1 receptor-associated protein interacts with transferrin receptor-1 and promotes its internalization (2022)
  • Author(s): Abe Eriko、Yamashita Akio、Hirota Keigo、Yamaji Takahiro、Azushima Kengo、Urate Shingo、Suzuki Toru、Tanaka Shohei、Taguchi Shinya、Tsukamoto Shunichiro、Uehara Tatsuki、Wakui Hiromichi、Tamura Kouichi、Takahashi Hidehisa
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 17376-17376
  • DOI: 10.1038/s41598-022-22343-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of tumor necrosis factor-α inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy (2021)
  • Author(s): Taguchi Shinya、Azushima Kengo、Yamaji Takahiro、Urate Shingo、Suzuki Toru、Abe Eriko、Tanaka Shohei、Tsukamoto Shunichiro、Kamimura Daisuke、Kinguchi Sho、Yamashita Akio、Wakui Hiromichi、Tamura Kouichi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 23587-23587
  • DOI: 10.1038/s41598-021-02864-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Impaired TCA Cycle Metabolism in Diabetic Nephropathy is Linked to Albuminuria and Kidney Injury. (2022)
  • Author(s): Azushima K, Kovalik JP, Yamaji T, Gurley SB, Coffman TM.
  • Organizer: The 29th Scientific Meeting of the International Society of Hypertension (ISH2022)
  • Int'l Joint Research
• [Presentation] Systemic ATRAP deletion exacerbates the development of diabetic nephropathy under angiotensin II stimulation in streptozotocin-diabetic mice. (2022)
  • Author(s): Taguchi S, Azushima K, Wakui H, Suzuki T, Urate S, Abe E, Tanaka S, Tsukamoto S, Tamura K.
  • Organizer: The 29th Scientific Meeting of the International Society of Hypertension (ISH2022)
  • Int'l Joint Research
• [Presentation] Beneficial Effects of Tumor Necrosis Factor-α Blockade in a Mouse Model of Diabetic Nephropathy. (2022)
  • Author(s): Yamaji T, Azushima K, Gurley SB, Coffman TM.
  • Organizer: WCN 2022 - The World Congress of Nephrology
  • Int'l Joint Research
• [Presentation] Functional Role of Tumor Necrosis Factor-α Pathway in Aristolochic Acid-induced Kidney Injury Model. (2021)
  • Author(s): Taguchi S, Azushima K, Wakui H, Yamaji T, Urate S, Suzuki T, Abe E, Tanaka S, Tsukamoto S, Yamashita A, Tamura K.
  • Organizer: Kidney Week 2021 (American Society of Nephrology Annual Meeting)
  • Int'l Joint Research
• [Presentation] Beneficial Effects of Tumor Necrosis Factor-α Blockade in a Mouse Model of Diabetic Nephropathy. (2021)
  • Author(s): Yamaji T, Azushima K, Gurley SB, Coffman TM.
  • Organizer: Kidney Week 2021 (American Society of Nephrology Annual Meeting)
  • Int'l Joint Research