Elucidation of the role of MRP8 through inflammation and ER stress in metabolic syndrome related nephropathy

• Project/Area Number: 17K16090
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Kumamoto University
• Principal Investigator: Mizumoto Teruhiko 熊本大学, 医学部附属病院, 特任助教 (80749193)
• Research Collaborator: Mukoyama Masashi ; Kuwabara Takashige ; Umemoto Syuro ; Fujimoto Daisuke ; Kanki Tomoko
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: MRP8 / 糖尿病性腎症 / マクロファージ / 糸球体障害 / 慢性炎症 / 糸球体上皮細胞 / 炎症

Outline of Final Research Achievements

In the previous report, MRP8 inflammation was reported by TLR4 mediated inflammation, but in this study we found that IRF3 mediated inflammation may be affected. However, the mechanism was unclear. We focused on exosomes and found that macrophages were activated in exosomes of mesangial cells. Furthermore, identification of drugs that suppress exosome-mediated inflammation was started. Out of 3300 compounds, 421 compounds that have achieved 40% or more suppression of inflammation in the primary screening are advanced to the second screening.

Academic Significance and Societal Importance of the Research Achievements

慢性腎臓病において進行を予防する手段は限られており、新規薬剤の開発が望まれている。糸球体内におけるエクソソームを介したマクロファージの炎症・ERストレスによる腎障害の進行の可能性を認めた。機序ははっきりしていないが、腎障害の進行を抑制する薬剤の同定を開始した。3300化合物の中から1次スクリーニングで、抑制率 40%以上が得られた421化合物を同定し、更なるスクリーニングを進めている。すでに臨床使用されている薬剤も含まれており、早期に慢性腎臓病に使用可能な薬剤となる可能性がある。

Research Products

• [Journal Article] Doxycycline attenuates cisplatin-induced acute kidney injury through pleiotropic effects (2018)
  • Author(s): Nakagawa T, Kakizoe Y, Iwata Y, Miyasato Y, Mizumoto T, Adachi M, Izumi Y, Kuwabara T, Suenaga N, Narita Y, Jono H, Saito H, Kitamura K, Mukoyama M
  • Journal Title: Am J Physiol Renal Physiol Volume: 315 Issue: 5 Pages: 1347-1357
  • DOI: 10.1152/ajprenal.00648.2017
  • Peer Reviewed
• [Presentation] 糸球体内クロストークにおけるメサンギウム細胞由来因子によるポドサイトERストレス応答の検討 (2018)
  • Author(s): 藤本大介、桒原孝成、梅本周朗、神吉智子、水本輝彦、早田学、泉裕一郎、柿添豊、向山政志
  • Organizer: 日本腎臓学会
• [Presentation] CKDにおけるMRP8の化学修飾の探索とその意義の検討 (2018)
  • Author(s): 神吉智子、桒原孝成、梅本周朗、藤本大介、水本輝彦、早田学、中山憲司、宮崎有、井上貴博、小川修、向山政志
  • Organizer: 日本腎臓学会
• [Presentation] Intraglomerular crosstalk between mesangial cells and podocytes inhibits normal ER-associated degradation processes and induces podocyte injury in diabetic nephropathy. (2018)
  • Author(s): Daisuke Fujimoto, Takashige Kuwabara, Yusuke Hata, Shuro Umemoto, Tomoko Kanki, Yoshihiko Nishiguchi, Teruhiko Mizumoto, Manabu Hayata, Yuichiro Izumi, Yutaka Kakizoe, Masashi Mukoyama
  • Organizer: American Society of Nephrology
  • Int'l Joint Research