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2019 Fiscal Year Annual Research Report

Elucidation of metabolic reprogramming in the kidney and development of novel therapeutic approaches utilizing HIF against kidney disease

Research Project

Project/Area Number 18H02824
Research InstitutionThe University of Tokyo

Principal Investigator

南学 正臣  東京大学, 医学部附属病院, 教授 (90311620)

Co-Investigator(Kenkyū-buntansha) 三村 維真理  東京大学, 医学部附属病院, 助教 (00727084)
平川 陽亮  東京大学, 医学部附属病院, 助教 (10780736)
稲城 玲子  東京大学, 医学部附属病院, 特任教授 (50232509)
田中 哲洋  東京大学, 医学部附属病院, 准教授 (90508079)
西 裕志  東京大学, 医学部附属病院, 助教 (90784174)
Project Period (FY) 2018-04-01 – 2021-03-31
Keywords低酸素 / HIF / 慢性腎臓病 / ミトコンドリア / CKD
Outline of Annual Research Achievements

慢性腎臓病 CKD の進行の final common pathway である尿細管間質の低酸素状態では、ミトコンドリアにおける酸化的リン酸化が障害される。低酸素に対する防御反応は、転写調節因子 hypoxia-inducible factor (HIF)が司っており、HIF は臓器への酸素供給を増加させるとともに細胞のエネルギー代謝を変化させて細胞機能を調節する(代謝リプログラミング)。本研究では、申請者らが世界に先駆けて展開してきた慢性腎臓病低酸素研究を発展・新展開させる。
これまで、培養尿細管細胞に対し低酸素、髙糖濃度、尿毒素などの様々な刺激を行って、代謝リプログラミングを評価してきた。これらの病的刺激における遺伝子発現変動について、エネルギー代謝に関連する分子の発現変動を中心に解析を進め、TCAサイクルを中心としたエネルギー代謝産物の測定を行うとともに、関連する分子の変動が代謝リプログラミングに果たす役割を検証している。更に、これらの病態における代謝リプログラミングにおける HIF の役割を明らかにするため、HIF を薬理学的に活性化することによるエネルギー代謝の変化を検証するとともに、並行してfinal common pathway としての長期的な影響をみるために、epigenomic な変化についても解析を進めた。
また、腎臓病モデル動物を作成し、代謝リプログラミングに関連すると考えられる遺伝子の発現調節および代謝産物の測定を行い、その病態生理学的意義を明らかにしている。更に、腎臓病モデル動物に対してHIF を薬理学的に活性化することにより、腎臓のエネルギー代謝の変化、酸化ストレスおよび低酸素状態への影響、病態の改善を調べ、その病態生理学的意義を解明している。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

研究は順調に進んでおり、複数の論文として成果発表することが出来ている。また、関連する新しい知見についても学会発表しており、現在論文化を急いでいる。

Strategy for Future Research Activity

ミトコンドリア障害において、代謝リプログラミングに加え、その下流で動く重要なシグナルカスケードについての詳細な検討を進めている。また、特に臓器間連関に注目し、様々な腎臓病モデルにおける代謝リプログラミングとそれに対するPHD阻害薬投与によりHIF の薬理学的活性化の影響の研究を進めている。特に、心腎連関 cardio-renal connection に重点を置いた解析を行っている。
尿細管特異的PHD(PHD-1,2,3)遺伝子改変動物についても研究が進んでおり、これを用いて代謝リプログラミングにおける PHD および HIF の役割を明らかにする実験を更に進める。

  • Research Products

    (30 results)

All 2020 2019 Other

All Int'l Joint Research (1 results) Journal Article (14 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 10 results,  Open Access: 4 results) Presentation (15 results) (of which Int'l Joint Research: 15 results,  Invited: 15 results)

  • [Int'l Joint Research] National Taiwan University(台湾)

    • Country Name
      その他の国・地域
    • Counterpart Institution
      National Taiwan University
  • [Journal Article] Prolyl Hydroxylase Domain Inhibitor Protects against Metabolic Disorders and Associated Kidney Disease in Obese Type 2 Diabetic Mice2020

    • Author(s)
      Sugahara Mai、Tanaka Shinji、Tanaka Tetsuhiro、Saito Hisako、Ishimoto Yu、Wakashima Takeshi、Ueda Masatoshi、Fukui Kenji、Shimizu Akira、Inagi Reiko、Yamauchi Toshimasa、Kadowaki Takashi、Nangaku Masaomi
    • Journal Title

      Journal of the American Society of Nephrology

      Volume: 31 Pages: 560~577

    • DOI

      10.1681/ASN.2019060582

  • [Journal Article] Effects of a prolyl hydroxylase inhibitor on kidney and cardiovascular complications in a rat model of chronic kidney disease2020

    • Author(s)
      Uchida Lisa、Tanaka Tetsuhiro、Saito Hisako、Sugahara Mai、Wakashima Takeshi、Fukui Kenji、Nangaku Masaomi
    • Journal Title

      American Journal of Physiology-Renal Physiology

      Volume: 318 Pages: F388~F401

    • DOI

      10.1152/ajprenal.00419.2019

  • [Journal Article] Prolyl hydroxylase inhibition protects the kidneys from ischemia via upregulation of glycogen storage2020

    • Author(s)
      Ito Marie、Tanaka Tetsuhiro、Ishii Taisuke、Wakashima Takeshi、Fukui Kenji、Nangaku Masaomi
    • Journal Title

      Kidney International

      Volume: 97 Pages: 687~701

    • DOI

      10.1016/j.kint.2019.10.020

  • [Journal Article] JTZ-951, an HIF prolyl hydroxylase inhibitor, suppresses renal interstitial fibroblast transformation and expression of fibrosis-related factors2020

    • Author(s)
      Wakashima Takeshi、Tanaka Tetsuhiro、Fukui Kenji、Komoda Yasumasa、Shinozaki Yuichi、Kobayashi Hatsue、Matsuo Akira、Nangaku Masaomi
    • Journal Title

      American Journal of Physiology-Renal Physiology

      Volume: 318 Pages: F14~F24

    • DOI

      10.1152/ajprenal.00323.2019

  • [Journal Article] Nuclear factor erythroid 2-related factor 2 as a treatment target of kidney diseases2020

    • Author(s)
      Ito Marie、Tanaka Tetsuhiro、Nangaku Masaomi
    • Journal Title

      Current Opinion in Nephrology and Hypertension

      Volume: 29 Pages: 128~135

    • DOI

      10.1097/MNH.0000000000000556

    • Peer Reviewed
  • [Journal Article] The oral hypoxia-inducible factor prolyl hydroxylase inhibitor enarodustat counteracts alterations in renal energy metabolism in the early stages of diabetic kidney disease2019

    • Author(s)
      Hasegawa Sho、Tanaka Tetsuhiro、Saito Tomoyuki、Fukui Kenji、Wakashima Takeshi、Susaki Etsuo A.、Ueda Hiroki R.、Nangaku Masaomi
    • Journal Title

      Kidney International

      Volume: in press Pages: in press

    • DOI

      10.1016/j.kint.2019.12.007

    • Peer Reviewed / Open Access
  • [Journal Article] Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury2019

    • Author(s)
      Maekawa Hiroshi、Inoue Tsuyoshi、Ouchi Haruki、Jao Tzu-Ming、Inoue Reiko、Nishi Hiroshi、Fujii Rie、Ishidate Fumiyoshi、Tanaka Tetsuhiro、Tanaka Yosuke、Hirokawa Nobutaka、Nangaku Masaomi、Inagi Reiko
    • Journal Title

      Cell Reports

      Volume: 29 Pages: 1261~1273.e6

    • DOI

      10.1016/j.celrep.2019.09.050

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Munc18-1-interacting protein 3 mitigates renal fibrosis through protection of tubular epithelial cells from apoptosis2019

    • Author(s)
      Nasu Kahori、Kawakami Takahisa、Shinohara Akinari、Sakamoto Takeharu、Nangaku Masaomi
    • Journal Title

      Nephrology Dialysis Transplantation

      Volume: in press Pages: in press

    • DOI

      10.1093/ndt/gfz177

    • Peer Reviewed
  • [Journal Article] JTZ-951 (enarodustat), a hypoxia-inducibe factor prolyl hydroxylase inhibitor, stabilizes HIF-α protein and induces erythropoiesis without effects on the function of vascular endothelial growth factor2019

    • Author(s)
      Fukui Kenji、Shinozaki Yuichi、Kobayashi Hatsue、Deai Katsuya、Yoshiuchi Hiromi、Matsui Takuya、Matsuo Akira、Matsushita Mutsuyoshi、Tanaka Tetsuhiro、Nangaku Masaomi
    • Journal Title

      European Journal of Pharmacology

      Volume: 859 Pages: 172532~172532

    • DOI

      10.1016/j.ejphar.2019.172532

    • Peer Reviewed
  • [Journal Article] Comprehensive three-dimensional analysis (CUBIC-kidney) visualizes abnormal renal sympathetic nerves after ischemia/reperfusion injury2019

    • Author(s)
      Hasegawa Sho、Susaki Etsuo A.、Tanaka Tetsuhiro、Komaba Hirotaka、Wada Takehiko、Fukagawa Masafumi、Ueda Hiroki R.、Nangaku Masaomi
    • Journal Title

      Kidney International

      Volume: 96 Pages: 129~138

    • DOI

      10.1016/j.kint.2019.02.011

    • Peer Reviewed
  • [Journal Article] Inhibition of prolyl hydroxylase domain (PHD) by JTZ-951 reduces obesity-related diseases in the liver, white adipose tissue, and kidney in mice with a high-fat diet2019

    • Author(s)
      Saito Hisako、Tanaka Tetsuhiro、Sugahara Mai、Tanaka Shinji、Fukui Kenji、Wakashima Takeshi、Nangaku Masaomi
    • Journal Title

      Laboratory Investigation

      Volume: 99 Pages: 1217~1232

    • DOI

      10.1038/s41374-019-0239-4

    • Peer Reviewed
  • [Journal Article] Prolyl hydroxylase domain inhibitors: a new era in the management of renal anemia2019

    • Author(s)
      Kurata Yu、Tanaka Tetsuhiro、Nangaku Masaomi
    • Journal Title

      Annals of Translational Medicine

      Volume: 7 Pages: S334~S334

    • DOI

      10.21037/atm.2019.09.118

    • Peer Reviewed / Open Access
  • [Journal Article] The role of oxidative stress and hypoxia in renal disease2019

    • Author(s)
      Honda Tomoko、Hirakawa Yosuke、Nangaku Masaomi
    • Journal Title

      Kidney Research and Clinical Practice

      Volume: 38 Pages: 414~426

    • DOI

      10.23876/j.krcp.19.063

    • Peer Reviewed / Open Access
  • [Journal Article] Hypoxia-Inducible Factor-Prolyl Hydroxylase Domain Inhibitors to Treat Anemia in Chronic Kidney Disease2019

    • Author(s)
      Sakashita Midori、Tanaka Tetsuhiro、Nangaku Masaomi
    • Journal Title

      Contributions to Nephrology

      Volume: 198 Pages: 112~123

    • DOI

      10.1159/000496531

    • Peer Reviewed
  • [Presentation] Kidney disease in Japan2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Berliner DialyseSeminar
    • Int'l Joint Research / Invited
  • [Presentation] Treatment strategies targeting hypoxia and oxidative stress - HIF and Nrf22019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      International Diabetes Federation Congress 2019
    • Int'l Joint Research / Invited
  • [Presentation] Oxygen metabolism in AKI and CKD2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      American Society of Nephrology
    • Int'l Joint Research / Invited
  • [Presentation] Mechanisms of AKI-on-CKD2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      2019 Asia-Pacific AKI to/on CKD Summit
    • Int'l Joint Research / Invited
  • [Presentation] Therapy of diabetic kidney disease: current and future2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      International Cogress of Diabetes and Metabolism 2019
    • Int'l Joint Research / Invited
  • [Presentation] The Molecular Mechanisms of AKI to CKD Transition and Its Clinical Implication2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      3rd Asia Pacific AKI CRRT Congress
    • Int'l Joint Research / Invited
  • [Presentation] New era of diabetic kidney disease2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Hong Kong Society of Nephrology
    • Int'l Joint Research / Invited
  • [Presentation] Update on anemia management in patients with CKD2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      APSN/HKSN CME course
    • Int'l Joint Research / Invited
  • [Presentation] AKI-to-CKD transition2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Chinese Society of Nephrology
    • Int'l Joint Research / Invited
  • [Presentation] Pathogenesis and treatment of CKD and its complications2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Asia Pacific Chapter Meeting of the ISPD
    • Int'l Joint Research / Invited
  • [Presentation] Anemia in CKD/ESKD: Is it still EPO?2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Asian Colloquium in Nephrology
    • Int'l Joint Research / Invited
  • [Presentation] Oxidative stress and hypoxia as novel therapeutic targets in kidney disease2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Korean Society of Nephrology
    • Int'l Joint Research / Invited
  • [Presentation] New therapies for diabetic nephropathy2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Nephrology Biennial Review Course of WCN 2019
    • Int'l Joint Research / Invited
  • [Presentation] HIF stabilizer in management of renal anemia2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Nephrology Biennial Review Course of WCN 2019
    • Int'l Joint Research / Invited
  • [Presentation] Targeting oxidative stress and inflammation in diabetic kidney disease2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Satellite Symposium of WCN 2019
    • Int'l Joint Research / Invited

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Published: 2021-01-27   Modified: 2022-08-22  

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