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Role of TRPV4/Connexin/Pannexin Interaction in Bladder Cystitis

Research Project

Project/Area Number 17K11176
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Urology
Research InstitutionUniversity of Yamanashi

Principal Investigator

YAO Jian  山梨大学, 大学院総合研究部, 准教授 (50303128)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
KeywordsTRPV4 / Connexin43 / 膀胱 / 間質性膀胱炎 / 酸化ストレス / インフラマソーム活性化 / 相互作用 / Cx43 / 間質膀胱炎 / inflammasome / NADPH oxidase / チャネル / TXNIP / シクロホスファミド / コネクシン / 免疫染色 / パネキシン
Outline of Final Research Achievements

TRPV4 and Cx43 channels are involved in the control of bladder contractile response. Blockade of each of them attenuates bladder overactivity in cyclophosphamide (CYP)-induced cystitis. It is unclear why two different channels similarly regulate bladder activity. We speculated that there existed a close interaction between TRPV4 and Cx43 channels under pathological situations, which contributed to the initiation and development of bladder abnormality. The aim of this study was to test this hypothesis.In a mouse model of CYP cystitis, TRPV4 and Cx43 proteins were found to be markedly increased. Further analysis revealed that the interaction between TRPV4 and Cx43 channels contributed to the regulation of the intracellular redox status and inflammasome activation. Collectively, our study indicates that the interaction between TRPV4 and Cx43 underlies the bladder abnormality through mechanisms involving its actions on the intracellular oxidative status and inflammatory response.

Academic Significance and Societal Importance of the Research Achievements

間質性膀胱炎とは、原因不明で、頻尿・尿意亢進・膀胱痛などの症状を呈する疾患である。患者の生活の質は膀胱刺激症状により大きく損なわれる。そのため、病態発症機序の解明、治療法の開発が望まれている。我々は、TRPV4及びCx43チャネルは膀胱の機能調節に重要であることから、両チャネル間の相互作用は膀胱炎の進展に寄与していることを想定し、研究を行った。動物及び細胞モデルにおいてTRPV4及びCx43チャネル間に緊密な相互作用が存在すること、また酸化ストレス及び炎症反応を調節していることを明らかにした。以上からTRPV4とCx43チャネル間の相互作用を標的とする治療法が有効であることを示している。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (21 results)

All 2020 2019 2018 2017 Other

All Journal Article (9 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 9 results,  Open Access: 2 results,  Acknowledgement Compliant: 2 results) Presentation (11 results) (of which Int'l Joint Research: 7 results,  Invited: 2 results) Remarks (1 results)

  • [Journal Article] Hydrogen Sulfide Mediates Tumor Cell Resistance to Thioredoxin Inhibitor2020

    • Author(s)
      Z. Mao, X. Yang, S. Mizutani, Y. Huang, Z. Zhang, H. Shinmori, K. Gao, J. Yao
    • Journal Title

      Frontiers in Oncology

      Volume: 10 Pages: 252-252

    • DOI

      10.3389/fonc.2020.00252

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Connexin43 Contributes to Inflammasome Activation and Lipopolysaccharide-Initiated Acute Renal Injury via Modulation of Intracellular Oxidative Status2019

    • Author(s)
      Huang Yanru、Mao Zhimin、Zhang Zhen、Obata Fumiko、Yang Xiawen、Zhang Xiling、Huang Yong、Mitsui Takahiko、Fan Jianglin、Takeda Masayuki、Yao Jian
    • Journal Title

      Antioxidants & Redox Signaling

      Volume: 31 Issue: 16 Pages: 1194-1212

    • DOI

      10.1089/ars.2018.7636

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hydrogen sulfide donor NaHS alters antibody structure and function via sulfhydration2019

    • Author(s)
      Zhang Zhen、Fang Xin、Yang Xiawen、Mitsui Takahiko、Huang Yanru、Mao Zhimin、Huang Yong、Takeda Masayuki、Yao Jian
    • Journal Title

      International Immunopharmacology

      Volume: 73 Pages: 491-501

    • DOI

      10.1016/j.intimp.2019.05.052

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Connexin43 Is Required for the Effective Activation of Spleen Cells and Immunoglobulin Production2019

    • Author(s)
      Huang Yanru、Mao Zhimin、Zhang Xiling、Yang Xiawen、Sawada Norifumi、Takeda Masayuki、Yao Jian
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Issue: 22 Pages: 5789-5789

    • DOI

      10.3390/ijms20225789

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pharmacological levels of hydrogen sulfide inhibit oxidative cell injury through regulating the redox state of thioredoxin2019

    • Author(s)
      Mao Z, Huang Y, Zhang Z, Yang X, Zhang X, Huang Y, Sawada N, Mitsui T, Takeda M, Yao J
    • Journal Title

      Free Radic Biol Med

      Volume: 11 Pages: 190-199

    • DOI

      10.1016/j.freeradbiomed.2019.01.009

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Induction of inactive TGF-β1 monomer formation by hydrogen sulfide contributes to its suppressive effects on Ang II- and TGF-β1-induced EMT in renal tubular epithelial cells2018

    • Author(s)
      Huang Y, Zhang Z, Huang Y, Mao Z, Yang X, Nakamura Y, Sawada N, Mitsui T, Takeda M, Yao J
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 501 Issue: 2 Pages: 534-540

    • DOI

      10.1016/j.bbrc.2018.05.032

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] The pivotal role of extracellular signal-regulated kinase in gap junction-mediated regulation of TXNIP2017

    • Author(s)
      Gao S, Zhang X, Gao K, Zhang Z, Huang Y, Yoda R, Yao J
    • Journal Title

      Cell Signal

      Volume: 38 Pages: 116-126

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Glutathione inhibits antibody and complement-mediated immunologic cell injury via multiple mechanisms.2017

    • Author(s)
      Zhang Z, Zhang X, Fang X, Niimi M, Huang Y, Piao H, Gao S, Fan J, Yao J.
    • Journal Title

      Redox Biol.

      Volume: 12 Pages: 571-581

    • DOI

      10.1016/j.redox.2017.03.030

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Carbenoxolone inhibits TRPV4 channel-initiated oxidative urothelial injury and ameliorates cyclophosphamide-induced bladder dysfunction2017

    • Author(s)
      Zhang X,Gao S,Tanaka M,Zhanq Z,Huanq Y,Mitsui T,Kamiyama M,Koizumi S,Fan J,Takeda M,Yao J
    • Journal Title

      J Cell Mol Med

      Volume: 2017 Issue: 9 Pages: 346-346

    • DOI

      10.1111/jcmm.13100

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Hydrogen sulfide inhibits adramycin-initiated glomerular pococyte injury via interference of Trx/ASK1/P38 signaling2019

    • Author(s)
      Jian Yao
    • Organizer
      ISN world conference of nephrology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Connexin43 regulates inflammasome activation and inflammatory cell injury through modulation of NADPH Oxidase-dependent redox signaling pathway2019

    • Author(s)
      Yanru Huang and Jian Yao
    • Organizer
      International Gap Junction Conference 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Role of Gap junctions in inflammasome activation and inflammatory renal diseases2019

    • Author(s)
      Jian Yao
    • Organizer
      第1回中国大連医科大学免疫及び代謝性疾患研究会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Hydrogen Sulfide Determines Tumor Cell Sensitivity to Thioredoxin Inhibitor PX-122019

    • Author(s)
      Zhimin Mao and Jian Yao
    • Organizer
      SfRBM2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Hydrogen sulfide counteracts angiotensin II-stimulated glomerular mesangial proliferation and matrix production via multiple mechanisms2018

    • Author(s)
      Zhen Zhang, Jian Yao
    • Organizer
      25th annual conference of SFRBM (society for free radical and biological medicine)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Hydrogen sulfide protects cells against oxidative stress through modifying the redox status of thioredoxin2018

    • Author(s)
      Zhimin Mao, Jian Yao
    • Organizer
      25th annual conference of SFRBM (society for free radical and biological medicine)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Connexin43 regulates inflammasome activation and LPS-initiated acute renal injury via modulation of cellular oxidative status2018

    • Author(s)
      Yanru Huang, Jian Yao
    • Organizer
      25th annual conference of SFRBM (society for free radical and biological medicine)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Gap junction-mediated regulation of redox signaling and oxidative cellular responses2017

    • Author(s)
      Yao Jian
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Hydrogen sulfide inhibits antibody- and complement-mediated immune responses via S-sulfhydration2017

    • Author(s)
      Zhen Zhang, Xiawen Yang, and Jian Yao
    • Organizer
      24th Annual Meeting of Free Radical Biology & Medicine
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Glutathione inhibits antibody-initiated and complement-dependent lysis of glomerular mesangial cells via multiple mechanisms2017

    • Author(s)
      Zhen Zhang, Jian Yao
    • Organizer
      第60回日本腎臓学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] The pivotal role of TRPV4 and Connexin43 channel transactivation in mediation of aminoglycoside-elicited renal tubular cell injury2017

    • Author(s)
      Xiling Zhang, Jian Yao
    • Organizer
      第60回日本腎臓学会学術総会
    • Related Report
      2017 Research-status Report
  • [Remarks] 山梨大学 研究者総覧

    • URL

      http://nerdb-re.yamanashi.ac.jp/Profiles/322/0032110/profile.html

    • Related Report
      2019 Annual Research Report 2018 Research-status Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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