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Clarifiation of CKD progression by regulating fibrotic microenvironment

Research Project

Project/Area Number 20K08605
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53040:Nephrology-related
Research InstitutionKanazawa University

Principal Investigator

SAKAI NORIHIKO  金沢大学, 附属病院, 准教授 (60377421)

Co-Investigator(Kenkyū-buntansha) 和田 隆志  金沢大学, その他部局等, その他 (40334784)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords線維化 / 線維芽細胞 / 接着斑 / 腎不全 / 慢性腎臓病
Outline of Research at the Start

臓器不全の共通進展機序である線維化の病理学的共通所見として、線維芽細胞集積と細胞外基質沈着がある。本研究は、線維化組織微小環境に着目して、線維化進展機序の解明および診断・治療法開発を目指す。申請者はこれまで、アクチン細胞骨格の生物学的役割に着目し、アクチン細胞骨格依存性の細胞内シグナル伝達機構が臓器線維化にはたす意義を報告してきた。近年、アクチン細胞骨格は、細胞と細胞外基質との接着装置である接着斑に結合することで、微小環境の形成に関与することが明らかとなっている。以上より、線維化組織微小環境に焦点をあて、アクチン細胞骨格依存性細胞内シグナル伝達の線維化にはたす意義を解明する。

Outline of Final Research Achievements

Fibrosis is characterized by an excessive wound healing response to organ damage, causing extracellular matrix deposition and accumulation of fibroblasts/myofibroblasts. In the process of enal failure, various renal diseases are characterized by taking a common process which is renal fibrosis. In this study, we attempted to elucidate the significance of cytoskeleton-dependent signal for renal fibrosis by regulating the biological properties of renal fibroblasts. As a result, it was revealed that the cytoskeleton-dependent MRTF-SRF signal by TGF-b1 in renal fibroblasts contributes to the expression of focal adhesion components and extracellular matrix such as colalgen and fibronectin. In addition, systemic MRTF-A- and fbroblast-specific MRTF-B- deficiency attenuates renal fibrosis by inhibiting the expression of focal adhesion components and extracellular matrix. Tese results suggest that MRTF-SRF signaling in fibroblast might be a target to combat renal fibrosis.

Academic Significance and Societal Importance of the Research Achievements

本研究では、細胞骨格に関連するMRTF-SRFシグナルが、腎臓を構成する線維芽細胞機能を調節することで腎不全の原因となる線維化に関与するかを試みた。その結果、腎線維芽細胞において、MRTF-SRFシグナルが、腎線維芽細胞を活性化させ、腎線維化進展に寄与することを明らかにした。これは腎障害の原因に関わらない共通進展機序であり、現在増加の一途を辿っている末期腎不全患者数の抑制につながる新規治療法開発につながることが期待される。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (21 results)

All 2023 2022 2021 2020

All Journal Article (14 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 14 results,  Open Access: 11 results) Presentation (7 results)

  • [Journal Article] Intra-brain and plasma levels of L-Serine are associated with cognitive status in patients with CKD. Kid Dis2023

    • Author(s)
      〇Iwata Y*, Nakade Y, Kinoshita M, Sabit H, Nakajima R, Furuichi K, Mita M, Nakane M, Sakai N, Kitajima S, Toyama T, Miyagawa T, Hara A, Shimizu M, Sato K, Oshima M, Nakagawa S, Yamamura Y, Ogura H, Koshino Y, Nakada M, Wada T.
    • Journal Title

      Kidney Dis (Basel) .

      Volume: 9 Issue: 2 Pages: 118-129

    • DOI

      10.1159/000527798

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increased levels of oral Streptococcus-derived D-alanine in patients with chronic kidney disease and diabetes mellitus.2022

    • Author(s)
      Nakade Y, Iwata Y*, Sakai N, Mita M, Nakane M, Hamase K, Suda W, Toyama T, Kitajima S, Hara A, Shimizu M, Ogushi C, Furuichi K, Koshino Y, Morita H, Hattori M, Wada T.
    • Journal Title

      Sci Rep

      Volume: 12 Issue: 1 Pages: 21773-21773

    • DOI

      10.1038/s41598-022-26175-1

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Deep learning analysis of clinical course of primary nephrotic syndrome: Japan Nephrotic syndrome cohort study (JNSCS).2022

    • Author(s)
      Kimura T, Yamamoto R, Yoshino M, Sakate R, Imai E, Maruyama S, Yokoyama H, Sugiyama H, Nitta K, Tsukamoto T, Uchida S, Takeda A, Sato T, Wada T, Hayashi H, Akai Y, Fukunaga M, Tsuruya K, Masutani K et al.
    • Journal Title

      Clinical and Experimental Nephrology

      Volume: 26 Issue: 4 Pages: 1170-1179

    • DOI

      10.1159/000527900

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Kif26b contributes to the progression of interstitial fibrosis via migration and myofibroblast differentiation in renal fibroblast2022

    • Author(s)
      Yamamura Yuta、Iwata Yasunori、Furuichi Kengo、Kato Takahiro、Yamamoto Naoki、Horikoshi Keisuke、Ogura Hisayuki、Sato Koichi、Oshima Megumi、Nakagawa Shiori、Miyagawa Taro、Kitajima Shinji、Toyama Tadashi、Hara Akinori、Sakai Norihiko、Shimizu Miho、Horike Shinichi、Daikoku Takiko、Nishinakamura Ryuichi、Wada Takashi
    • Journal Title

      The FASEB Journal

      Volume: 36 Issue: 11

    • DOI

      10.1096/fj.202200355r

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ablation of lysophosphatidic acid receptor 1 attenuates hypertrophic cardiomyopathy in a mouse model2022

    • Author(s)
      Axelsson Raja Anna、Wakimoto Hiroko、DeLaughter Daniel M.、Reichart Daniel、Gorham Joshua、Conner David A.、Lun Mingyue、Probst Clemens K.、Sakai Norihiko、et al.
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 119 Issue: 28

    • DOI

      10.1073/pnas.2204174119

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cyclin-dependent kinase 4-related tubular epithelial cell proliferation is regulated by Paired box gene 2 in renal ischemia-reperfusion injury2022

    • Author(s)
      Sako K, Furuichi K, Makiishi S, Yamamura Y, Okumura T, Le T, Kitajima S, Toyama T, Hara A, Iwata Y, Sakai N, Shimizu M, Niimura F, Matsusaka T, Kaneko S, Wada T.
    • Journal Title

      Kidney International

      Volume: - Issue: 1 Pages: 45-57

    • DOI

      10.1016/j.kint.2022.03.022

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Anti-fibrotic potential of erythropoietin signaling on bone marrow derived fibrotic cell2021

    • Author(s)
      Iwata Yasunori、Sakai Norihiko、Nakajima Yuki、Oshima Megumi、Nakagawa-Yoneda Shiori、Ogura Hisayuki、Sato Koichi、Minami Taichiro、Kitajima Shinji、Toyama Tadashi、Yamamura Yuta、Miyagawa Taro、Hara Akinori、Shimizu Miho、Furuichi Kengo、Wada Takashi
    • Journal Title

      BMC Nephrology

      Volume: 22 Issue: 1

    • DOI

      10.1186/s12882-021-02411-0

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] D-Serine inhibits the attachment and biofilm formation of methicillin-resistant Staphylococcus aureus2021

    • Author(s)
      Iwata Y, Sakai N, Yoneda I, Senda Y, Sakai-Takemori Y, Oshima M, Nakagawa-Yoneda S, Ogura H, Sato K, Minami T, Kitajima S, Toyama T, Yamamura Y, Miyagawa T, Hara A, Shimizu M, Furuichi K, Matsushima K, Wada T.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 22 Pages: 50-56

    • DOI

      10.1016/j.bbrc.2020.12.078

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Carnitine/organic cation transporter 1 precipitates the progression of interstitial fibrosis through oxidative stress in diabetic nephropathy in mice2021

    • Author(s)
      Makiishi Shohei、Furuichi Kengo、Yamamura Yuta、Sako Keisuke、Shinozaki Yasuyuki、Toyama Tadashi、Kitajima Shinji、Iwata Yasunori、Sakai Norihiko、Shimizu Miho、Hirose-Sugiura Tomoko、Kaneko Shuichi、Kato Yukio、Wada Takashi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 9093-9093

    • DOI

      10.1038/s41598-021-88724-4

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of candidate PAX2-regulated genes implicated in human kidney development2021

    • Author(s)
      Yuta Yamamura, Kengo Furuichi, Yasuhiro Murakawa, Shigeki Hirabayashi, Masahito Yoshihara, Keisuke Sako, Shinji Kitajima, Tadashi Toyama, Yasunori Iwata, Norihiko Sakai, Kazuyoshi Hosomichi, Philip M Murphy, Atsushi Tajima, Keisuke Okita, Kenji Osafune, Shuichi Kaneko, Takashi Wada
    • Journal Title

      Scientific reports

      Volume: 11 Issue: 1 Pages: 9123-9123

    • DOI

      10.1038/s41598-021-88743-1

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Higher serum levels of autotaxin and phosphatidylserine-specific phospholipase A 1 in patients with lupus nephritis2021

    • Author(s)
      Iwata Y, Kitajima S, Yamahana J, Shimomura S, Yoneda-Nakagawa S, Sakai N, Furuichi K, Ogura H, Sato K, Toyama T, Yamamura Y, Miyagawa T, Hara A, Shimizu M, Ohkawa R, Kurano M, Yatomi Y, Wada T.
    • Journal Title

      Int J Rheum Dis.

      Volume: 24 Issue: 2 Pages: 231-239

    • DOI

      10.1111/1756-185x.14031

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Trehalose ameliorates peritoneal fibrosis by promoting Snail degradation and inhibiting mesothelial-to-mesenchymal transition in mesothelial cells2020

    • Author(s)
      Miyake Taito、Sakai Norihiko、Tamai Akira、Sato Koichi、Kamikawa Yasutaka、Miyagawa Taro、Ogura Hisayuki、Yamamura Yuta、Oshima Megumi、Nakagawa Shiori、Sagara Akihiro、Shinozaki Yasuyuki、Toyama Tadashi、Kitajima Shinji、Hara Akinori、Iwata Yasunori、Shimizu Miho、Furuichi Kengo、Kaneko Shuichi、Wada Takashi
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 14292-14292

    • DOI

      10.1038/s41598-020-71230-4

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The increased frequency of methicillin-resistant Staphylococcus aureus with low MIC of beta-lactam antibiotics isolated from hospitalized patients2020

    • Author(s)
      Iwata Y、Sakai N、Yoneda I、Satou K、Furuichi K、Senda Y、Sakai-Takemori Y、Wada T、Fujita S、Ogura H、Sato K、Minami T、Yamaguchi K、Kitajima S、Toyama T、Yamamura Y、Miyagawa T、Hara A、Shimizu M、Sakai Y、Ikeo K、Shichino S、Ueha S、Nakajima T、Matsushima K、Wada T
    • Journal Title

      Journal of Infection and Chemotherapy

      Volume: 26 Issue: 6 Pages: 604-610

    • DOI

      10.1016/j.jiac.2020.01.016

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Propagermanium administration for patients with type 2 diabetes and nephropathy: A randomized pilot trial2020

    • Author(s)
      Hara Akinori、Shimizu Miho、Hamaguchi Erika、Kakuda Hirokazu、Ikeda Kenzo、Okumura Toshiya、Kitagawa Kiyoki、Koshino Yoshitaka、Kobayashi Motoo、Takasawa Kazuya、Hisada Yukimasa、Toyama Tadashi、Iwata Yasunori、Sakai Norihiko、Wada Takashi
    • Journal Title

      Endocrinology, Diabetes & Metabolism

      Volume: 3 Issue: 3

    • DOI

      10.1002/edm2.159

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 腎線維化における接着斑形成を介した細胞骨格関連シグナルの意義2023

    • Author(s)
      坂井宣彦、山村雄太、湯浅貴博、小倉央行、大島恵、中川詩織、宮川太郎北島信治、遠山直志、原章規、清水美保、和田隆志、岩田恭宜
    • Organizer
      日本リウマチ学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 糖尿病性腎症における腎イベント発症例の心血管予後に、高血圧と腎組織における細動脈内膜肥厚が及ぼす影響2021

    • Author(s)
      清水美保、宮川太郎、北島信治、遠山直志、原章規、岩田恭宜、坂井宣彦、和田隆志
    • Organizer
      第66回日本透析医学会学術集会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] ISN/RPS改訂組織分類によるループス腎炎の長期予後の検討2021

    • Author(s)
      中川詩織、岩田恭宜、大島恵、小倉央行、佐藤晃一、山村雄太、宮川太郎、北島信治、遠山直志、原章規、坂井宣彦、清水美保、和田隆志
    • Organizer
      第65回日本リウマチ学会総会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 造血器腫瘍性疾患における腎障害2020

    • Author(s)
      坂井宣彦、和田隆志
    • Organizer
      日本腎臓学会西部学術大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 発症機序に基づいた、薬剤性腎障害へのアプローチ2020

    • Author(s)
      坂井宣彦、和田隆志
    • Organizer
      日本内科学会北陸地方会
    • Related Report
      2020 Research-status Report
  • [Presentation] RPGNを呈するループス腎炎に対するアフェレシス療法の意義2020

    • Author(s)
      中川詩織、北島信治、加治貴彰、大島恵、小倉央行、佐藤晃一、山村雄太、宮川太郎、遠山直志、原章規、北川清樹、岩田恭宜、坂井宣彦、清水美保、和田隆志
    • Organizer
      日本アフェレシス学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 短時間腹膜平衡試験による腹膜機能評価および予後予測2020

    • Author(s)
      堀越 慶輔,坂井 宣彦,小倉 央行,佐藤 晃一,宮川 太郎,山内 博行, 北島 信治,遠山 直志,原 章規,岩田 恭宜,清水 美保,大田 聡, 石田 陽一,和田 隆志
    • Organizer
      日本透析医学会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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