Treatment targeting RAGE signal by microRNA in diabetic nephropathy

• Project/Area Number: 18K08220
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Juntendo University
• Principal Investigator: Hagiwara Shinji 順天堂大学, 医学部, 准教授 (70445568)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 糖尿病性腎症 / miRNA / RAGE / PAI-1 / microRNA / 糖尿病 / 腎線維化 / マイクロRNA / Diaph1

Outline of Final Research Achievements

Advanced glycation end product (AGE) promotes fibrosis via AGE receptor (RAGE) and is greatly involved in the development of diabetic nephropathy. We focused on miR-199a, which was highly expressed in the mesangial cells extracted from RAGE knockout mouse that was shown to be protected against diabetic nephropathy. Overexpression of miR-199a in mouse mesangial cells decreased PAI-1 expression, and knocking down of miR-199a increased PAI-1 expression. In addition, TGF-β stimulation reduced the expression of miRNA-199a. As a result of comparing the expression levels of fibrotic markers, it was suggested that miR-199a has an antifibrotic effect in mesangial cells. It has been predicted that PAI-1 is the target gene for miRNA-199a from the database (TargetScan) and will be confirmed using the 3'UTR reporter assay in the future.

Academic Significance and Societal Importance of the Research Achievements

miRNAは細胞シグナルを調整するメディエーターであり、腎障害が出現する以前にそのプロファイルに変化が認められるため、そのプロファイルの解析により早期に腎障害を予測できる可能性がある。また糖尿病性腎症の線維化に関連するmiRNAを解析することで、早期診断およびmiRNAを用いた新しい治療法を開発することは、末期腎不全に対する腎代替療法の医療費削減にも有用であると考えられる。
申請者らこれまで糖尿病性腎症に対して腎保護作用が示されているRAGE KOマウスにおいて過剰発現したmiRNAを同定しており、着目したmiRNAの糖尿病性腎症における影響を検証することは非常に興味深いと考えている。

Research Products

• [Journal Article] Potential Targeting of Renal Fibrosis in Diabetic Kidney Disease Using MicroRNAs (2020)
  • Author(s): Sakuma Hiroko、Hagiwara Shinji、Kantharidis Phillip、Gohda Tomohito、Suzuki Yusuke
  • Journal Title: Frontiers in Pharmacology Volume: 11 Pages: 1-9
  • DOI: 10.3389/fphar.2020.587689
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] THE EXPRESSION AND THE ROLE OF MICRORNA IN RAGE KNOCK OUT MOUSE MESANGIAL CELLS (2019)
  • Author(s): Shinji Hagiwara, Yusuke Suzuki, Tomohito Gohda, Kazuhiko Funabiki, Mark Cooper, Phillip Kantharidis
  • Organizer: World Congress of Nephrology 2019
  • Int'l Joint Research
• [Presentation] THE EXPRESSION AND THE ROLE OF MICRORNA IN RAGE KNOCK OUT MOUSE MESANGIAL CELLS (2019)
  • Author(s): Shinji Hagiwara
  • Organizer: World Congress of Nephrology 2019
  • Int'l Joint Research
• [Book] 糖尿病性腎臓病の病態と治療（第３章病態生理：C．線維化・細胞外基質・microRNA ） (2021)
  • Author(s): 萩原晋二, 富野 康日己 (監) / 和田 隆志 , 合田 朋仁 (編)
  • Total Pages: 270
  • Publisher: 中外医学社
  • ISBN: 9784498224681