Strategies aimed at modulating autophagy for treating kidney diseases

• Project/Area Number: 15H06371
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Kidney internal medicine
• Research Institution: Osaka University
• Principal Investigator: Yamamoto Takeshi 大阪大学, 医学部附属病院, 医員 (20756994)
• Project Period (FY): 2015-08-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: オートファジー / フラックス / 近位尿細管 / 老化 / Rubicon / クロロキン / 尿細管 / エベロリムス

Outline of Final Research Achievements

Autophagy plays an essential role for cellular homeostasis. Here, we established the methods for monitoring autophagic flux in vivo by using GFP-LC3 transgenic mice and tamoxifen-inducible proximal tubule-specific autophagy-deficient mice. Using the methods, we investigated the impact of altered autophagic flux in kidney aging. Furthermore, we newly established mice models in which autophagic flux is genetically (Rubicon, a Beclin1-interacting negative regulator for autophagosome-lysosome fusion, knockout mice) and pharmacologically(omega-3 fatty acid, EPA) enhanced. Proximal tubule-specific Rubicon knockout mice showed high autophagic flux in basal and stressed conditions and exhibited significant improvement of kidney injury in some choronic kidey disease models. Also, EPA attenuated renal lipotoxicity by improving autophagic flux in obese mice kidneys. Modulating autophagic flux would be a potentially important therapeutic target for regulating progression of kidney diseases.

Research Products

• [Journal Article] Time-dependent dysregulation of autophagy: Implications in aging and mitochondrial homeostasis in the kidney proximal tubule. (2016)
  • Author(s): Yamamoto T, Takabatake Y, Kimura T, Takahashi A, Namba T, Matsuda J, Minami S, Kaimori JY, Matsui I, Kitamura H, Matsusaka T, Niimura F, Yanagita M, Isaka Y, Rakugi H.
  • Journal Title: Autophagy Volume: 12 Issue: 5 Pages: 801-13
  • DOI: 10.1080/15548627.2016.1159376
  • NAID: 40021034920
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 加齢によるオートファジー活性の変化がミトコンドリア機能低下を介して腎老化を引き起こす (2016)
  • Author(s): 山本毅士
  • Journal Title: 日本腎臓学会誌 Volume: 58 Pages: 1238-1242
• [Presentation] Time-dependent dysregulation of autophagy: Implications in aging and mitochondrial homeostasis in the kidney proximal tubule (2016)
  • Author(s): 山本毅士
  • Organizer: 第38回腎臓セミナー・Nexus Japan
  • Place of Presentation: 東京
  • Year and Date: 2016-08-27
• [Presentation] 加齢によるオートファジー活性の変化がミトコンドリア機能低下を介して腎老化を引き起こす (2015)
  • Author(s): 山本毅士
  • Organizer: 第6回分子腎臓フォーラム
  • Place of Presentation: 大阪
  • Year and Date: 2015-09-05