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Analyses for molecular mechanisms of dipeptidyl peptidase III-targeted peptide that deteriorates diabetic kidney disease

Research Project

Project/Area Number 21K06854
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49010:Pathological biochemistry-related
Research InstitutionShiga University of Medical Science

Principal Investigator

Shimizu Akio  滋賀医科大学, 医学部, 助教 (30769279)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords糖尿病性腎臓病 / 2型糖尿病 / ペプチド / ジペプチジルペプチダーゼIII / DPPIII / 血管障害 / C3補体
Outline of Research at the Start

糖尿病で増加しDPPIIIによって分解されるペプチドが持つ作用機序とそのペプチドによる糖尿病性腎臓病の増悪メカニズムを明らかにすることを目的とする。その成果を元に、糖尿病性腎臓病に対する新規治療開発をトランスレーショナル研究として進展させる。

Outline of Final Research Achievements

Dipeptidyl peptidase III (DPPIII) treatment in diabetic db/db mice suppressed the DM-induced cardiac diastolic dysfunctions and renal injury without alteration of the blood glucose level. The treatment inhibited inflammatory cell infiltration and fibrosis in the heart, and blocked the increase in albuminuria by attenuating the disruption of the glomerular microvasculature and inhibiting the effacement of podocyte foot processes in the kidney. The beneficial role of DPPIII was mediated by the cleavage of a cytotoxic peptide, which was increased in db/db mice compared with normal mice. The peptide had an anaphylatoxin-like effect. The effect was dependent on its interaction with the C3a receptor and protein kinase C-mediated RhoA activation downstream of the receptor in endothelial cells. In conclusion, DPPIII plays a protective role in the heart and kidney in the DM animal model through cleavage of the peptide that is a part of C3.

Academic Significance and Societal Importance of the Research Achievements

本研究は、DPPIIIが2型糖尿病モデルマウスであるdb/dbマウスにおいて、糖尿病性腎症の増悪は、DPP III投与によって、血糖値、血圧、心機能に変動なく有意に抑制されることを見出した。つまり、DPP IIIは血糖や血圧の調節とは独立して糸球体保護作用を発揮し、糖尿病性腎症を抑制する全く新しい効果を有していることが判明した。糖尿病の治療は発達しているものの、糖尿病性腎症は増加傾向にある。このことは、糖尿病性腎症の克服には単純に血糖値を正常化するだけでは不十分であり、新たな治療法の開発、創薬が必要であることを意味している。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (23 results)

All 2024 2023 2022 2021

All Journal Article (8 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 8 results,  Open Access: 6 results) Presentation (14 results) Book (1 results)

  • [Journal Article] Establishment of a novel mouse model of renal artery coiling-based chronic hypoperfusion-related kidney injury2024

    • Author(s)
      Imamura-Uehara Yoshimi、Yasuda-Yamahara Mako、Kuwagata Shogo、Yamahara Kosuke、Yoshibayashi Mamoru、Tanaka-Sasaki Yuki、Shimizu Akio、Ogita Hisakazu、Chin-Kanasaki Masami、Kume Shinji
    • Journal Title

      Biochemistry and Biophysics Reports

      Volume: 37 Pages: 101607-101607

    • DOI

      10.1016/j.bbrep.2023.101607

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Null mutation of exocyst complex component 3-like does not affect vascular development in mice2024

    • Author(s)
      Takashima Satsuki、Okamura Eiichi、Ichiyama Yusuke、Nishi Kiyoto、Shimizu Akio、Watanabe Chisato、Muto Masanaga、Matsumoto Shoma、Tsukiyama-Fujii Setsuko、Tsukiyama Tomoyuki、Ogita Hisakazu、Nishi Eiichiro、Ohji Masahito、Sugiyama Fumihiro、Takahashi Satoru、Mizuno Seiya、Mizutani Ken-ichi、Ema Masatsugu
    • Journal Title

      Experimental Animals

      Volume: 73 Issue: 1 Pages: 93-100

    • DOI

      10.1538/expanim.23-0105

    • ISSN
      0007-5124, 1341-1357, 1881-7122
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Generation of a familial hypercholesterolemia model in non-human primate2023

    • Author(s)
      Sato Akira、Tsukiyama Tomoyuki、Komeno Masahiro、Iwatani Chizuru、Tsuchiya Hideaki、Kawamoto Ikuo、Murase Mitsuru、Nakagawa Takahiro、Itagaki Iori、Seita Yasunari、Matsumoto Shoma、Nakaya Masataka、Shimizu Akio、Yamada Atsushi、Ema Masatsugu、Ogita Hisakazu
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 15649-15649

    • DOI

      10.1038/s41598-023-42763-1

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel cardiovascular protective effects of RhoA signaling and its therapeutic implications2023

    • Author(s)
      Soh Joanne Ern Chi、Shimizu Akio、Sato Akira、Ogita Hisakazu
    • Journal Title

      Biochemical Pharmacology

      Volume: 218 Pages: 115899-115899

    • DOI

      10.1016/j.bcp.2023.115899

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RhoA rescues cardiac senescence by regulating Parkin-mediated mitophagy2023

    • Author(s)
      Soh Joanne Ern Chi、Shimizu Akio、Molla Md Rasel、Zankov Dimitar P.、Nguyen Le Kim Chi、Khan Mahbubur Rahman、Tesega Wondwossen Wale、Chen Si、Tojo Misa、Ito Yoshito、Sato Akira、Hitosugi Masahito、Miyagawa Shigeru、Ogita Hisakazu
    • Journal Title

      Journal of Biological Chemistry

      Volume: 299 Issue: 3 Pages: 102993-102993

    • DOI

      10.1016/j.jbc.2023.102993

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Vascular smooth muscle RhoA counteracts abdominal aortic aneurysm formation by modulating MAP4K4 activity2022

    • Author(s)
      Molla Md Rasel、Shimizu Akio、Komeno Masahiro、Rahman Nor Idayu A.、Soh Joanne Ern Chi、Nguyen Le Kim Chi、Khan Mahbubur Rahman、Tesega Wondwossen Wale、Chen Si、Pang Xiaoling、Tanaka-Okamoto Miki、Takashima Noriyuki、Sato Akira、Suzuki Tomoaki、Ogita Hisakazu
    • Journal Title

      Communications Biology

      Volume: 5 Issue: 1 Pages: 1071-1071

    • DOI

      10.1038/s42003-022-04042-z

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Transmembrane protein 168 mutation reduces cardiomyocyte cell surface expression of Nav1.5 through αB-crystallin intracellular dynamics2021

    • Author(s)
      Nguyen LKC, Shimizu A, Soh JEC, Komeno M, Sato A, Ogita H
    • Journal Title

      J Biochem

      Volume: 170 Issue: 5 Pages: 577-585

    • DOI

      10.1093/jb/mvab066

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cell‐to‐cell contact‐mediated regulation of tumor behavior in the tumor microenvironment2021

    • Author(s)
      Sato A, Rahman NIA, Shimizu A, Ogita H
    • Journal Title

      Cancer Sci

      Volume: 112 Issue: 10 Pages: 4005-4012

    • DOI

      10.1111/cas.15114

    • NAID

      120007146544

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Afadin-mediated regulation of vascular smooth muscle cell contraction via the Gq-phospholipase Cβ axis to enhance calcium signaling2023

    • Author(s)
      Md Mahbubur Rahman Khan, Akira Sato, Akio Shimizu, Hisakazu Ogita
    • Organizer
      日本生化学会近畿支部例会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Employing static electric machine to suppress the progression of diabetic kidney disease by minimizing type 2 diabetes-induced oxidative stress2023

    • Author(s)
      Le Kim Chi Nguyen, Akio Shimizu, Hisakazu Ogita
    • Organizer
      日本生化学会近畿支部例会
    • Related Report
      2023 Annual Research Report
  • [Presentation] The developing embryo requires endothelial RhoA for its angiogenesis and survival2023

    • Author(s)
      Wondwossen Wale Tesega, Akio Shimizu, Hisakazu Ogita
    • Organizer
      日本生化学会近畿支部例会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 心血管系におけるRhoAの新機能とその分子作用機序2023

    • Author(s)
      清水 昭男
    • Organizer
      日本生化学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Novel Protective Role of RhoA in the Senescence Heart by Regulating Parkin-mediated Mitophagy2023

    • Author(s)
      Joanne Ern Chi Soh, Akio Shimizu, Rasel Md Molla, Hisakazu Ogita
    • Organizer
      第87 回日本循環器学会学術集会(福岡国際会議場)
    • Related Report
      2022 Research-status Report
  • [Presentation] Role of Afadin in vascular smooth muscle contraction via the Gq-phospholipase Cb axis to enhance calcium signaling2022

    • Author(s)
      Md Mahbubur Rahman Khan,Akira Sato,Akio Shimizu,Masahiro Komeno,Md Rasel Molla, Hisakazu Ogita
    • Organizer
      第68回日本生化学会近畿支部例会(滋賀医科大学)
    • Related Report
      2022 Research-status Report
  • [Presentation] RhoA regulates senescence heart by maintaining mitochondrial function via Parkin-dependent mitophagy2022

    • Author(s)
      Joanne Ern Chi Soh,Akio Shimizu,Hisakazu Ogita
    • Organizer
      第68回日本生化学会近畿支部例会(滋賀医科大学)
    • Related Report
      2022 Research-status Report
  • [Presentation] Transmembrane protein 168 mutation that associates with Brugada syndrome recruits αBcrystallin to reduce cardiac Nav1.5 expression on the cardiomyocyte surface2022

    • Author(s)
      Le Kim Chi Nguyen, Akio Shimizu,Akira Sato,Hisakazu Ogita
    • Organizer
      第68回日本生化学会近畿支部例会(滋賀医科大学)
    • Related Report
      2022 Research-status Report
  • [Presentation] Vascular Smooth Muscle RhoA Confers Protection Against Abdominal Aortic Aneurysm Formation by Inhibiting MAP4K4 Activity2022

    • Author(s)
      Md Rasel Molla,Akio Shimizu,Akira Sato,Tomoaki Suzuki, Hisakazu Ogita
    • Organizer
      第68回日本生化学会近畿支部例会(滋賀医科大学)
    • Related Report
      2022 Research-status Report
  • [Presentation] Role of transmembrane protein 168 mutation in Brugada syndrome by alteration in subcellular localization of αB-crystallin to modulate sodium channel Nav1.5 surface expression in cardiomyocytes2022

    • Author(s)
      Le Kim Chi Nguyen, Akio Shimizu, Akira Sato, Hisakazu Ogita
    • Organizer
      第95回日本生化学会大会(名古屋国際会議場)
    • Related Report
      2022 Research-status Report
  • [Presentation] Novel protective role of RhoA in vascular smooth muscle cells against aortic aneurysm formation2022

    • Author(s)
      Md Rasel Molla, Akio Shimizu, Akira Sato, Hisakazu Ogita
    • Organizer
      第86回日本循環器学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Dipeptidyl peptidase IIIの糖尿病性腎臓病抑制機序2021

    • Author(s)
      米野雅大, Md Rasel Molla, 清水昭男, 扇田久和
    • Organizer
      第67回日本生化学会近畿支部例会
    • Related Report
      2021 Research-status Report
  • [Presentation] RhoA Protects Senescence Heart by Preserving Mitochondrial Function via Parkin2021

    • Author(s)
      Joanne Ern Chi Soh, Akio Shimizu, Md Rasel Molla, Hisakazu Ogita
    • Organizer
      第5回日本循環器学会基礎研究フォーラム
    • Related Report
      2021 Research-status Report
  • [Presentation] ジペプチジルペプチダーゼIIIが糖尿病性腎臓病を抑制する作用機序2021

    • Author(s)
      米野雅大, Md Rasel Molla, 清水昭男, 扇田久和
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Research-status Report
  • [Book] モデル動物の作製と利用-循環器疾患2021 <上巻>2021

    • Author(s)
      清水昭男、扇田久和
    • Total Pages
      594
    • Publisher
      株式会社エル・アイ・シー
    • ISBN
      9784900487581
    • Related Report
      2021 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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