Functional analysis of novel microRNA inhibiting tubulointerstitial fibrosis.

• Project/Area Number: 16K19477
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: Mimura Imari 東京大学, 医学部附属病院, 助教 (00727084)
• Project Period (FY): 2017-02-07 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 低酸素 / エピジェネティクス / 腎線維化 / ヒストン修飾 / 慢性腎不全 / ヒストン修飾酵素阻害薬

Outline of Final Research Achievements

The main researcher of this project found that Dznep, which inhibits H3K27me3, repressed the tubulointerstitial fibrosis in chronic kidney disease models. Genome-wide analysis using next generation sequencing revealed that Timp2 (tissue inhibitor of metalloproteinase2) inhibited the fibrosis-associated genes under the hypoxic condition and Dznep administration. The researcher also identified the down-regulated microRNAs under hypoxia by analyzing the small RNA-seq.

Academic Significance and Societal Importance of the Research Achievements

腎尿細管間質の線維化には慢性的な低酸素状態が病態の増悪に寄与するが、そのメカニズムを抑制する画期的な治療薬はいまだ開発されていない。本研究では、ヒストン修飾阻害薬を投与することで線維化を抑制する分子メカニズムをエピジェネティックな視点から明らかにした。ヒトに投与する際には、全身性の投与の場合、標的臓器以外への副作用や、標的となる腎臓までの薬剤デリバリーシステムの開発など、まだ問題点はあるものの、新規治療薬の開発につながる重要な研究である。

Research Products

• [Journal Article] Nutcracker Syndrome with the Superimposition of Thin Basement Membrane Syndrome (2019)
  • Author(s): Hirakawa Y, et al.
  • Journal Title: Internal Medicine Volume: 58 Issue: 3 Pages: 411-414
  • DOI: 10.2169/internalmedicine.1433-18
  • NAID: 130007585605
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-02-01
  • Peer Reviewed
• [Journal Article] Are women more susceptible to renal dysfunction? (2019)
  • Author(s): Imari Mimura
  • Journal Title: Kidney International Volume: 96 Issue: 6 Pages: 1275-1277
  • DOI: 10.1016/j.kint.2019.08.030
  • Peer Reviewed
• [Journal Article] Intravital phosphorescence lifetime imaging of the renal cortex accurately measures renal hypoxia. (2018)
  • Author(s): Hirakawa Y, Mizukami K, Yoshihara T, Takahashi I, Khulan P, Honda T, Mimura I, Tanaka T, Tobita S, Nangaku M.
  • Journal Title: Kidney Int. Volume: 印刷中 Issue: 6 Pages: 1483-1489
  • DOI: 10.1016/j.kint.2018.01.015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The Lasker Prize award 2018: histones "tail" the story. (2018)
  • Author(s): Mimura I, Nangaku M.
  • Journal Title: Kidney International Volume: 94 Issue: 6 Pages: 1032-1034
  • DOI: 10.1016/j.kint.2018.10.005
  • Peer Reviewed
• [Journal Article] Kidney aging: an irresistible slope. (2018)
  • Author(s): Mimura I
  • Journal Title: Kidney International Volume: 95 Issue: 3 Pages: 492-494
  • DOI: 10.1016/j.kint.2018.11.036
  • Peer Reviewed
• [Journal Article] Genome-wide analysis revealed that DZNep reduces tubulointerstitial fibrosis via down-regulation of pro-fibrotic genes. (2018)
  • Author(s): Mimura I, Hirakawa Y, Kanki Y, Nakaki R, Suzuki Y, Tanaka T, Aburatani H, Nangaku M.
  • Journal Title: Sci Rep. Volume: 28 Issue: 1 Pages: 3779-3779
  • DOI: 10.1038/s41598-018-22180-5
  • Peer Reviewed / Open Access
• [Presentation] Dznep, a histone modifier, reduces tubulointerstitial fibrosis via decrease of TIMP2. (2019)
  • Author(s): Imari Mimura, Yosuke Hirakawa, Yasuharu Kanki, Tetsuhiro Tanaka, Hiroyuki Aburatani, Masaomi Nangaku
  • Organizer: ヨーロッパ腎臓学会（ERA-EDTA）2019
  • Int'l Joint Research
• [Presentation] クロマチンリモデリング因子INO80は腎尿細管細胞のアポトーシスを抑制する (2019)
  • Author(s): 三浦 理加, 三村 維真理, 佐藤 大, 田中 哲洋, 南学 正臣
  • Organizer: 第62回日本腎臓学会学術総会
• [Presentation] 低酸素下で腎尿細管細胞のアポトーシスを抑制するクロマチンリモデリング因子INO80の分子メカニズムの解明 (2019)
  • Author(s): 三村 維真理, 三浦 理加,佐藤 大, 田中 哲洋, 南学 正臣
  • Organizer: 低酸素研究会
• [Presentation] INO80 inhibits tubulointerstitial apoptosis under hypoxia. (2019)
  • Author(s): Rika Miura, Imari Mimura, Dai Sato, Tetsuhiro Tanaka, Masaomi Nangaku
  • Organizer: アメリカ腎臓学会（American Society of Nephrology)
  • Int'l Joint Research
• [Presentation] クロマチンリモデリング因子INO80は腎尿細管細胞のアポトーシスを抑制する (2019)
  • Author(s): 三村維真理, 三浦理加，佐藤大, 田中哲洋, 南学正臣
  • Organizer: 第42回日本分子生物学会総会
• [Presentation] 低酸素下におけるエピジェネティックな遺伝子発現制御とその機能解明 (2018)
  • Author(s): 三村 維真理
  • Organizer: 日本生化学大会
  • Invited
• [Presentation] ヒストン修飾阻害薬Dznepによる腎尿細管間質線維化抑制のメカニズムの解明 (2018)
  • Author(s): 三村 維真理、平川 陽亮、神吉 康晴、田中 哲洋、鈴木 穣、油谷 浩幸、南学 正臣
  • Organizer: 日本分子生物学会
• [Presentation] Identification of novel epigenetic factors in chronic kidney diseases. (2018)
  • Author(s): 三村 維真理
  • Organizer: Hypoxia Research Meeting 2018
  • Int'l Joint Research / Invited
• [Presentation] Dznep reduces tubulointerstitial fibrosis via decrease of TIMP2. (2018)
  • Author(s): Mimura I, Hirakawa Y, Kanki Y, Suzuki Y, Aburatani H, Tetsuhiro Tanaka, Nangaku M.
  • Organizer: International Society of Nephrology Frontiers 2018.
  • Int'l Joint Research
• [Funded Workshop] Hypoxia Research Meeting2018 (2018)