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2019 Fiscal Year Annual Research Report

Role of local inflammation in the kidney for the development and progression of chronic kidney disease and its regulation toward novel therapeutic strategy

Research Project

Project/Area Number 17K09706
Research InstitutionKumamoto University

Principal Investigator

向山 政志  熊本大学, 大学院生命科学研究部(医), 教授 (40270558)

Project Period (FY) 2017-04-01 – 2020-03-31
Keywords慢性腎臓病 / 糖尿病性腎臓病 / 慢性炎症 / 細胞連関 / マクロファージ / メサンギウム / ポドサイト / ERストレス
Outline of Annual Research Achievements

慢性腎炎や糖尿病性腎臓病(DKD)などの慢性腎臓病(CKD)発症・進展の病態解明を目指して、腎内慢性炎症を中心に検討を進めてきた。
マクロファージ(Mφ)由来myeloid-related protein 8 (MRP8)は自己免疫や腫瘍などに重要とされる。CKDでの意義を検討するため、骨髄由来細胞特異的MRP8欠損(MyM8KO)マウスで半月体形成性腎炎を惹起させ、腎病変が軽減することを示した。その機序として、MφのM1優位な形質獲得とMincle発現を抑止し、遊走性・接着性を抑制することで糸球体傷害改善に寄与する可能性を報告した。また、DKDではメサンギウム病変とポドサイト(Podo)傷害は必須で、病態進展に両細胞の連関の存在とERストレスの関与が示唆される。メサンギウム細胞培養上清(MC-sup)刺激のPodoへの影響、及び小胞体関連分解(ERAD)阻害薬(ERADi)がPodoに与える影響を評価したところ、培養PodoへのMC-sup刺激は、ERAD因子の発現を抑制、アポトーシスを誘導した。これらは高糖濃度条件下MC-supで増強した。PodoへのERADi投与は同様の反応を再現し、糖尿病db/dbマウスへのERADi投与で糸球体病変とアルブミン尿が増悪した。すなわち、高糖濃度条件に暴露されたMCとのクロストークがPodoの正常なERADプロセスを阻害し、腎症を悪化させる可能性が示唆された。
さらに、維持血液透析患者を対象に、血中の炎症関連液性因子Angptl2濃度およびMRP8/14 heterodimer濃度と予後との関連を検討した。その結果、Angptl2高値は生命予後不良と有意に相関することがわかった。一方、血中MRP8/14濃度は血中Pと関連し、P低値群では影響がないが、P高値群においてMRP8/14高値が明らかな生命予後不良を予測することが明らかとなった。

  • Research Products

    (21 results)

All 2020 2019

All Journal Article (9 results) (of which Peer Reviewed: 9 results,  Open Access: 5 results) Presentation (12 results) (of which Int'l Joint Research: 9 results,  Invited: 3 results)

  • [Journal Article] The predictive role of serum calprotectin on mortality in hemodialysis patients with high phosphoremia2020

    • Author(s)
      Kanki Tomoko、Kuwabara Takashige、Morinaga Jun、Fukami Hirotaka、Umemoto Shuro、Fujimoto Daisuke、Mizumoto Teruhiko、Hayata Manabu、Kakizoe Yutaka、Izumi Yuichiro、Tajiri Saeko、Tajiri Tetsuya、Kitamura Kenichiro、Mukoyama Masashi
    • Journal Title

      BMC Nephrology

      Volume: 21 Pages: 158

    • DOI

      10.1186/s12882-020-01812-x

    • Peer Reviewed / Open Access
  • [Journal Article] Protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes2020

    • Author(s)
      Yoshibayashi Mamoru、Kume Shinji、Yasuda-Yamahara Mako、Yamahara Kosuke、Takeda Naoko、Osawa Norihisa、Chin-Kanasaki Masami、Nakae Yuki、Yokoi Hideki、Mukoyama Masashi、Asanuma Katsuhiko、Maegawa Hiroshi、Araki Shin-ichi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 525 Pages: 319~325

    • DOI

      10.1016/j.bbrc.2020.02.088

    • Peer Reviewed
  • [Journal Article] Ablation of Myeloid Cell MRP8 Ameliorates Nephrotoxic Serum-induced Glomerulonephritis by Affecting Macrophage Characterization through Intraglomerular Crosstalk2020

    • Author(s)
      Hata Yusuke、Kuwabara Takashige、Mori Kiyoshi、Kan Youngna、Sato Yuki、Umemoto Shuro、Fujimoto Daisuke、Kanki Tomoko、Nishiguchi Yoshihiko、Yokoi Hideki、Kakizoe Yutaka、Izumi Yuichiro、Yanagita Motoko、Mukoyama Masashi
    • Journal Title

      Scientific Reports

      Volume: 10 Pages: 3056

    • DOI

      10.1038/s41598-020-59970-9

    • Peer Reviewed / Open Access
  • [Journal Article] Circulating angiopoietin-like protein 2 levels and mortality risk in patients receiving maintenance hemodialysis: a prospective cohort study2020

    • Author(s)
      Morinaga J、Kakuma T、Fukami H、Hayata M、Uchimura K、Mizumoto T、Kakizoe Y、Miyoshi T、Shiraishi N、Adachi M、Izumi Y、Kuwabara T、Okadome Y、Sato M、Horiguchi H、Sugizaki T、Kadomatsu T、Miyata K、Tajiri S、Tajiri T、Tomita K、Kitamura K、Oike Y、Mukoya
    • Journal Title

      Nephrology Dialysis Transplantation

      Volume: 35 Pages: 854~860

    • DOI

      10.1093/ndt/gfz236

    • Peer Reviewed
  • [Journal Article] Usefulness of the quantitative measurement of urine protein at a community-based health checkup: A cross-sectional study.2020

    • Author(s)
      M. Naruse、M. Mukoyama、J. Morinaga、M. Miyazaki、K. Iseki、K. Yamagata
    • Journal Title

      Clinical and Experimental Nephrology

      Volume: 24 Pages: 45~52

    • DOI

      10.1007/s10157- 019-01789-4

    • Peer Reviewed
  • [Journal Article] Autosomal dominant Alport syndrome due to a COL4A4 mutation with an additional ESPN variant detected by whole-exome analysis.2020

    • Author(s)
      Y. Izumi、A. Hamaguchi、R. Miura、T. Nakagawa、M. Nakagawa、K. Saida、N. Miyake、Y. Nagayoshi、Y. Kakizoe、T. Miyoshi、Y. Kohda、Y. Misumi、N. Matsumoto、Y. Ando、M. Mukoyama
    • Journal Title

      CEN Case Reports

      Volume: 9 Pages: 59~64

    • DOI

      10.1007/s13730-019-00429-w

    • Peer Reviewed / Open Access
  • [Journal Article] Edoxaban Exerts Antioxidant Effects Through FXa Inhibition and Direct Radical-Scavenging Activity2019

    • Author(s)
      Narita Yuki、Hamamura Kana、Kashiyama Mami、Utsumi Sara、Kakizoe Yutaka、Kondo Yuki、Ishitsuka Yoichi、Jono Hirofumi、Irie Tetsumi、Mukoyama Masashi、Saito Hideyuki、Kadowaki Daisuke、Hirata Sumio、Kitamura Kenichiro
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Pages: 4140~4140

    • DOI

      10.3390/ijms20174140

    • Peer Reviewed / Open Access
  • [Journal Article] Insufficiency of urinary acid excretion of overweight or obese patients with chronic kidney disease and its involvement with renal tubular injury2019

    • Author(s)
      Eguchi Koji、Izumi Yuichiro、Nakayama Yushi、Inoue Hideki、Marume Takahiro、Matsuo Naomi、Hiramatsu Akiko、Ono Makoto、Kakizoe Yutaka、Kuwabara Takashige、Nonoguchi Hiroshi、Mukoyama Masashi
    • Journal Title

      Nephrology

      Volume: 24 Pages: 1131~1141

    • DOI

      10.1111/nep.13553

    • Peer Reviewed
  • [Journal Article] Roles of matricellular CCN2 deposited by osteocytes in osteoclastogenesis and osteoblast differentiation2019

    • Author(s)
      Nishida Takashi、Kubota Satoshi、Yokoi Hideki、Mukoyama Masashi、Takigawa Masaharu
    • Journal Title

      Scientific Reports

      Volume: 9 Pages: 10913

    • DOI

      10.1038/s41598-019-47285-3

    • Peer Reviewed / Open Access
  • [Presentation] Intraglomerular crosstalk between mesangial cells and podocytes inhibits normal ER-associated degradation processes and induces podocyte injury in diabetic kidney disease.2019

    • Author(s)
      Daisuke Fujimoto
    • Organizer
      ISN World Congress of Nephrology
    • Int'l Joint Research
  • [Presentation] Potential role of MRP8 in glomerular injury through intraglomerular crosstalk affecting macrophage characterization.2019

    • Author(s)
      Yusuke Hata
    • Organizer
      ISN World Congress of Nephrology
    • Int'l Joint Research
  • [Presentation] Investigation of the role of renal tubular NFAT5 in renal fibrogenesis caused by unilateral ureteral obstruction.2019

    • Author(s)
      Makoto Ono
    • Organizer
      Annual Meeting of the American society of Nephrology
    • Int'l Joint Research
  • [Presentation] Ablation of MRP8 in myeloid cells ameliorates glomerulonephritis by affecting macrophage characterization.2019

    • Author(s)
      Yusuke Hata
    • Organizer
      Annual Meeting of the American society of Nephrology
    • Int'l Joint Research
  • [Presentation] Intraglomerular crosstalk between mesangial cells and podocytes inhibits normal ER-associated degradation processes and induces podocyte injury in diabetes.2019

    • Author(s)
      Daisuke Fujimoto
    • Organizer
      Annual Meeting of the American society of Nephrology
    • Int'l Joint Research
  • [Presentation] The predictive role of serum MRP8/14 (S100A8/A9) on mortality in hemodialysis patients.2019

    • Author(s)
      Tomoko Kanki
    • Organizer
      Annual Meeting of the American society of Nephrology
    • Int'l Joint Research
  • [Presentation] Circulating angiopoietin-like protein 2 levels and mortality risk in patients receiving maintenance hemodialysis: a prospective cohort study.2019

    • Author(s)
      Jun Morinaga
    • Organizer
      Annual Meeting of the American society of Nephrology
    • Int'l Joint Research
  • [Presentation] Urinary plasmin plays pathogenic roles for the development of hypertension in Dahl salt-sensitive rats.2019

    • Author(s)
      Yasunobu Iwata
    • Organizer
      Annual Meeting of the American society of Nephrology
    • Int'l Joint Research
  • [Presentation] Regulation of Rhcg protein in the intercalated cells of the outer medullary collecting ducts by aldosterone.2019

    • Author(s)
      Yuichiro Izumi
    • Organizer
      Annual Meeting of the American society of Nephrology
    • Int'l Joint Research
  • [Presentation] 高血圧・腎臓病の病態と臓器連関:Na利尿ペプチド系および炎症・プロテアーゼの意義2019

    • Author(s)
      向山政志
    • Organizer
      第62回日本腎臓学会学術総会
    • Invited
  • [Presentation] メタボリック症候群や慢性腎臓病におけるホルモン異常と高血圧2019

    • Author(s)
      柿添 豊、向山政志
    • Organizer
      第42回日本高血圧学会総会
    • Invited
  • [Presentation] 高血圧、CKDの病態と臓器連関:内分泌因子と炎症の意義2019

    • Author(s)
      向山政志
    • Organizer
      第13回日本腎臓病薬物療法学会学術集会・総会
    • Invited

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Published: 2021-01-27  

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