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2018 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) 田中 哲洋  東京大学, 医学部附属病院, 講師 (90508079)
稲城 玲子  東京大学, 医学部附属病院, 特任教授 (50232509)
三村 維真理  東京大学, 医学部附属病院, 助教 (00727084)
西 裕志  東京大学, 医学部附属病院, 助教 (90784174)
平川 陽亮  東京大学, 医学部附属病院, 助教 (10780736)
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)。本申請では、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、腎臓病の病態生理についてミトコンドリア障害とエネルギー代謝の側面からの理解を深め、腎臓の障害における低酸素に伴うエピゲノム変化を調べるとともに、HIF活性化による代謝リプログラミングの病態生理学的役割を調べている。今年度は糖尿病性腎臓病のモデル動物における代謝障害について、imaging mass-spectrometry などの手法を用いて解析し、TCAサイクルの異常と酸化ストレスが生じており、それが治療により改善することを見いだし、論文化した。また、虚血状態における尿細管細胞の代謝障害と薬理学的な HIF の活性化による代謝リプログラミングに関する新しい知見や遺伝性腎疾患におけるミトコンドリア障害に関する新たな知見を得て、学会発表した。更に、HIF の活性化による肝臓および脂肪組織における代謝リプログラミングについても新しい知見を得て、論文化している。一方、エピゲノムの変化に関する研究も順調に進めており、腎障害モデル動物におけるエピゲノムの変化に薬理学的に介入することにより、虚血に起因する長期的な腎臓の線維化が改善できることを見いだし、これを論文化した。

Current Status of Research Progress
Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

エピゲノムの変化に関する研究および代謝リプログラミングに関する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。並行して、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 HIF の薬理学的活性化の影響について、多臓器連関の観点からの研究を進めている。

  • Research Products

    (41 results)

All 2019 2018 Other

All Int'l Joint Research (2 results) Journal Article (13 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 13 results,  Open Access: 4 results) Presentation (26 results) (of which Int'l Joint Research: 19 results,  Invited: 17 results)

  • [Int'l Joint Research] Mark D Okusa, Alessia Fornoni/University of Virginia/University of Miami(米国)

    • Country Name
      U.S.A.
    • Counterpart Institution
      Mark D Okusa, Alessia Fornoni/University of Virginia/University of Miami
  • [Int'l Joint Research] Thitinun Anusornvongchai/Lerdsin General Hospital(タイ)

    • Country Name
      THAILAND
    • Counterpart Institution
      Thitinun Anusornvongchai/Lerdsin General Hospital
  • [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] 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
  • [Journal Article] A Placebo-Controlled, Randomized Trial of Enarodustat in Patients with Chronic Kidney Disease Followed by Long-Term Trial2019

    • Author(s)
      Akizawa Tadao、Nangaku Masaomi、Yamaguchi Takuhiro、Arai Masanobu、Koretomo Ryosuke、Matsui Atsushi、Hirakata Hideki
    • Journal Title

      American Journal of Nephrology

      Volume: 49 Pages: 165~174

    • DOI

      10.1159/000496929

    • Peer Reviewed / Open Access
  • [Journal Article] Non-canonical cholinergic anti-inflammatory pathway-mediated activation of peritoneal macrophages induces Hes1 and blocks ischemia/reperfusion injury in the kidney2019

    • Author(s)
      Inoue Tsuyoshi、Abe Chikara、Kohro Takahide、Tanaka Shinji、Huang Liping、Yao Junlan、Zheng Shuqiu、Ye Hong、Inagi Reiko、Stornetta Ruth L.、Rosin Diane L.、Nangaku Masaomi、Wada Youichiro、Okusa Mark D.
    • Journal Title

      Kidney International

      Volume: 95 Pages: 563~576

    • DOI

      10.1016/j.kint.2018.09.020

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] ATF6α downregulation of PPARα promotes lipotoxicity-induced tubulointerstitial fibrosis2019

    • Author(s)
      Jao Tzu-Ming、Nangaku Masaomi、Wu Chia-Hsien、Sugahara Mai、Saito Hisako、Maekawa Hiroshi、Ishimoto Yu、Aoe Mari、Inoue Tsuyoshi、Tanaka Tetsuhiro、Staels Bart、Mori Kazutoshi、Inagi Reiko
    • Journal Title

      Kidney International

      Volume: 95 Pages: 577~589

    • DOI

      10.1016/j.kint.2018.09.023

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Sodium?glucose cotransporter 2 inhibition normalizes glucose metabolism and suppresses oxidative stress in the kidneys of diabetic mice2018

    • Author(s)
      Tanaka Shinji、Sugiura Yuki、Saito Hisako、Sugahara Mai、Higashijima Yoshiki、Yamaguchi Junna、Inagi Reiko、Suematsu Makoto、Nangaku Masaomi、Tanaka Tetsuhiro
    • Journal Title

      Kidney International

      Volume: 94 Pages: 912~925

    • DOI

      10.1016/j.kint.2018.04.025

    • Peer Reviewed
  • [Journal Article] Palmitate deranges erythropoietin production via transcription factor ATF4 activation of unfolded protein response2018

    • Author(s)
      Anusornvongchai Thitinun、Nangaku Masaomi、Jao Tzu-Ming、Wu Chia-Hsien、Ishimoto Yu、Maekawa Hiroshi、Tanaka Tetsuhiro、Shimizu Akira、Yamamoto Masayuki、Suzuki Norio、Sassa Ryoji、Inagi Reiko
    • Journal Title

      Kidney International

      Volume: 94 Pages: 536~550

    • DOI

      10.1016/j.kint.2018.03.011

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Persistent expression of neutrophil gelatinase-associated lipocalin and M2 macrophage markers and chronic fibrosis after acute kidney injury2018

    • Author(s)
      Saito Hisako、Tanaka Tetsuhiro、Tanaka Shinji、Higashijima Yoshiki、Yamaguchi Junna、Sugahara Mai、Ito Marie、Uchida Lisa、Hasegawa Sho、Wakashima Takeshi、Fukui Kenji、Nangaku Masaomi
    • Journal Title

      Physiological Reports

      Volume: 6 Pages: e13707~e13707

    • DOI

      10.14814/phy2.13707

    • Peer Reviewed / Open Access
  • [Journal Article] Intravital phosphorescence lifetime imaging of the renal cortex accurately measures renal hypoxia2018

    • Author(s)
      Hirakawa Yosuke、Mizukami Kiichi、Yoshihara Toshitada、Takahashi Ippei、Khulan Purevsuren、Honda Tomoko、Mimura Imari、Tanaka Tetsuhiro、Tobita Seiji、Nangaku Masaomi
    • Journal Title

      Kidney International

      Volume: 93 Pages: 1483~1489

    • DOI

      10.1016/j.kint.2018.01.015

    • Peer Reviewed
  • [Journal Article] Genome-wide analysis revealed that DZNep reduces tubulointerstitial fibrosis via down-regulation of pro-fibrotic genes2018

    • Author(s)
      Mimura Imari、Hirakawa Yosuke、Kanki Yasuharu、Nakaki Ryo、Suzuki Yutaka、Tanaka Tetsuhiro、Aburatani Hiroyuki、Nangaku Masaomi
    • Journal Title

      Scientific Reports

      Volume: 8 Pages: 3779

    • DOI

      10.1038/s41598-018-22180-5

    • Peer Reviewed / Open Access
  • [Journal Article] Hypoxia-inducible factor stabilizers for treating anemia of chronic kidney disease2018

    • Author(s)
      Hasegawa Sho、Tanaka Tetsuhiro、Nangaku Masaomi
    • Journal Title

      Current Opinion in Nephrology and Hypertension

      Volume: 27 Pages: 331~338

    • DOI

      10.1097/MNH.0000000000000431

    • Peer Reviewed
  • [Journal Article] Introduction: Kidney Disease and Cardiovascular Disease2018

    • Author(s)
      Nangaku Masaomi
    • Journal Title

      Seminars in Nephrology

      Volume: 38 Pages: 207~207

    • DOI

      10.1016/j.semnephrol.2018.03.001

    • Peer Reviewed
  • [Presentation] The Role of Hypoxia and HIF in Tubule Injury2019

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Keystone Symposium: Unraveling the Secrets of Kidney Disease
    • Int'l Joint Research / Invited
  • [Presentation] Nrf2活性化薬の可能性2018

    • Author(s)
      南学正臣
    • Organizer
      第30回日本糖尿病性腎症研究会
    • Invited
  • [Presentation] AKI to CKD Transition2018

    • Author(s)
      Masaomi Nangaku
    • Organizer
      American Society of Nephrology
    • Int'l Joint Research / Invited
  • [Presentation] The Burden of CKD; Challenges and Successes2018

    • Author(s)
      Masaomi Nangaku
    • Organizer
      American Society of Nephrology
    • Int'l Joint Research / Invited
  • [Presentation] Mitochondrial DNA Leakage Causes Inflammation via the cGAS-STING Axis in Cisplatin-Mediated Tubular Damage2018

    • Author(s)
      Maekawa H, Jao T-Z, Inoue R, Nishi H, Inoue T, Nangaku M, Inagi R.
    • Organizer
      American Society of Nephrology
    • Int'l Joint Research
  • [Presentation] Efficacy and Safety of Daprodustat on Anemia Management in Japanese Hemodialysis Patients Not Using Erythropoiesis-Stimulating Agents2018

    • Author(s)
      Fujii T, Tsubakihara Y, Akizawa T, Nangaku M, Onoue T, Yonekawa T, Endo Y, Cobitz AR.
    • Organizer
      American Society of Nephrology
    • Int'l Joint Research
  • [Presentation] Randomized, Placebo-Controlled Phase 2 Trials of Vadadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor (HIF-PHI), to Treat Anemia of CKD2018

    • Author(s)
      Nangaku M, Khawaja Z, Luo W, Garafola S, deGoma E, Komatsu Y.
    • Organizer
      American Society of Nephrology
    • Int'l Joint Research
  • [Presentation] Whole-Kidney Three-Dimensional Imaging Reveals the Progression of Renal Sympathetic Denervation after Ischemia-Reperfusion Injury2018

    • Author(s)
      Hasegawa S, Fukagawa M, Ueda HR, Nangaku M, Tanaka T, Susaki EA, Komaba H, Wada T, Saito H, Sugahara M, Uchida L, Ito M.
    • Organizer
      American Society of Nephrology
    • Int'l Joint Research
  • [Presentation] Multiple, Systemic Effects of PHD Inhibitors Signify an Anti-Fibrotic and Anti-Inflammatory Impact on Cardiovascular Complications in the Remnant Kidney2018

    • Author(s)
      Uchida L, Tanaka T, Saito H, Sugahara M, Fukui K, Wakashima T, Nangaku M.
    • Organizer
      American Society of Nephrology
    • Int'l Joint Research
  • [Presentation] Mitochondrial Morphological Abnormality in Cyst Epithelial Cells of Autosomal Dominant Polycystic Kidney Disease Patients2018

    • Author(s)
      Ishimoto Y, Shimizu A, Kugita M, Nagao S, Honda K, Inagi R, Nangaku M, Nishio S, Kawano H, Horie S, Kasahara T, Osafune K, Hoshino J, Ubara Y.
    • Organizer
      American Society of Nephrology
    • Int'l Joint Research
  • [Presentation] PHD Inhibition Reduces Reactive Oxidative Stress in In Vitro Ischemia Model2018

    • Author(s)
      Ito M, Tanaka T, Wakashima T, Nangaku M, Fukui K.
    • Organizer
      American Society of Nephrology
    • Int'l Joint Research
  • [Presentation] Hes1, a Newly Identified Downstream Mediator of α7nAChR on Macrophages in the Cholinergic Anti-Inflammatory Pathway, Plays a Protective Role in AKI2018

    • Author(s)
      Inoue T, Abe C, Tanaka S, Rosin DL, Nangaku M, Wada Y, Okusa MD.
    • Organizer
      American Society of Nephrology
    • Int'l Joint Research
  • [Presentation] ATF6α and PPARα Cross-Talk Provides New Insights into Lipotoxicity-Induced Tubulointerstitial Fibrosis2018

    • Author(s)
      Jao T-M, Inoue T, Sugahara M, Maekawa H, Ishimoto Y, Tanaka T, Nangaku M, Inagi R.
    • Organizer
      American Society of Nephrology
    • Int'l Joint Research
  • [Presentation] Anti-oxidative stress therapy against DKD2018

    • Author(s)
      南学正臣
    • Organizer
      第33回日本糖尿病合併症学会
    • Invited
  • [Presentation] The Molecular Machanisms of AKI to CKD Transition and Its Clinical Implication2018

    • Author(s)
      Masaomi Nangaku
    • Organizer
      2nd Asia-Pacific AKI CRRT Congress
    • Int'l Joint Research / Invited
  • [Presentation] Can Biomarker Based Management for AKI Improve Outcomes?2018

    • Author(s)
      Masaomi Nangaku
    • Organizer
      2nd Asia-Pacific AKI CRRT Congress
    • Int'l Joint Research / Invited
  • [Presentation] The AKI to CKD Continuum: a Clinical Perspective2018

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Hong Kong Society of Nephrology
    • Int'l Joint Research / Invited
  • [Presentation] Anemia treatment in CKD: Update2018

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Malaysian Society of Nephrology
    • Int'l Joint Research / Invited
  • [Presentation] Diabetic nephropathy: Is there anything new?2018

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Malaysian Society of Nephrology
    • Int'l Joint Research / Invited
  • [Presentation] 慢性腎臓病における心・血管障害2018

    • Author(s)
      南学正臣
    • Organizer
      第10回日本下肢救済・足病学会学術集会
    • Invited
  • [Presentation] 腎性貧血とHIF2018

    • Author(s)
      南学正臣
    • Organizer
      第10回日本下肢救済・足病学会学術集会
    • Invited
  • [Presentation] 慢性腎不全治療薬の開発 その課題と今後への期待2018

    • Author(s)
      南学正臣
    • Organizer
      第61回日本腎臓学会
    • Invited
  • [Presentation] 糖尿病性腎臓病(DKD):新たな疾患概念:オーバービュー2018

    • Author(s)
      南学正臣
    • Organizer
      第61回日本腎臓学会
    • Invited
  • [Presentation] 糖尿病性腎臓病DKDの抑制を目指して2018

    • Author(s)
      南学正臣
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Invited
  • [Presentation] Update of management of diabetic nephropathy2018

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Korean Soceity of Nephrology
    • Int'l Joint Research / Invited
  • [Presentation] New insights into AKI to CKD continuum and the role of maladaptive repair2018

    • Author(s)
      Masaomi Nangaku
    • Organizer
      Korean Soceity of Nephrology
    • Int'l Joint Research / Invited

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Published: 2019-12-27  

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