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Development of a new treatment for diabetic nephropathy by siRNA delivery using nanocarriers

Research Project

Project/Area Number 18K19533
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 53:Organ-based internal medicine and related fields
Research InstitutionThe University of Tokyo

Principal Investigator

Toshiro Fujita  東京大学, 先端科学技術研究センター, 名誉教授 (10114125)

Co-Investigator(Kenkyū-buntansha) 丸茂 丈史  東京大学, 先端科学技術研究センター, 特任准教授 (70265817)
Project Period (FY) 2018-06-29 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Keywords糖尿病性腎症 / エピジェネティクス / DNAメチル化 / ナノキャリア
Outline of Final Research Achievements

Because the progression of diabetic nephropathy is difficult to interfere with, it was thought that epigenetic modifications to renal constituent cells were involved in its development, but the details were unclear. In this study, we show that DNA methylation of the promoter of the Tgfb1 gene, which induces fibrosis and inflammation, occurs in renal mesangium cells of diabetic mouse models, and that the increased expression of the Tgfb1 gene is involved in the progression of nephropathy, indicating a new mechanism of diabetic nephropathy progression. A series of studies showed that cell-specific DNA methylation of the kidney is a promising predictive marker as well as a therapeutic target for diabetic nephropathy.

Academic Significance and Societal Importance of the Research Achievements

本研究は、糖尿病性腎症の進行には腎構成細胞におけるエピジェネティック修飾が深く関与することを証明した。すなわち糖尿病性腎症の抑制のためには、エピジェネティク治療薬の開発と共に、有用な早期マーカーの探索とそれによる予防が重要であることを実証したものであり、糖尿病による腎機能障害の医療に貢献するものと期待される

Report

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

    (34 results)

All 2020 2019 2018 Other

All Journal Article (9 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 4 results) Presentation (22 results) (of which Int'l Joint Research: 6 results,  Invited: 6 results) Remarks (3 results)

  • [Journal Article] Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency2020

    • Author(s)
      Kawarazaki W, Mizuno R, Nishimoto M, Ayuzawa N, Hirohama D, Ueda K, Kawakami-Mori F, Oba S, Marumo T and Fujita. T.
    • Journal Title

      J Clin Invest

      Volume: -

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Two mineralocorticoid receptor-mediated mechanisms of pendrin activation in distal nephrons2020

    • Author(s)
      Ayuzawa N, Nishimoto M, Ueda K, Hirohama D, Kawarazaki W, Shimosawa T, Marumo T, Fujita T.
    • Journal Title

      J Am Soc Nephrol.

      Volume: 31 Issue: 4 Pages: 748

    • DOI

      10.1681/asn.2019080804

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 腎臓病の進展に関わるエピジェネティクス2020

    • Author(s)
      丸茂丈史
    • Journal Title

      医学のあゆみ

      Volume: 272 Pages: 75-79

    • Related Report
      2019 Annual Research Report
  • [Journal Article] 代謝疾患とエピゲノム2020

    • Author(s)
      丸茂丈史
    • Journal Title

      遺伝子医学

      Volume: 10 Pages: 49-52

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Evaluation of the pathophysiological mechanisms of salt-sensitive hypertension2019

    • Author(s)
      Hirohama D, Fujita T.
    • Journal Title

      Hypertens Res.

      Volume: 42 Issue: 12 Pages: 1848

    • DOI

      10.1038/s41440-019-0332-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mineralocorticoid receptor blockade suppresses dietary salt-induced ACEI/ARB-resistant albuminuria in non-diabetic hypertension: a sub-analysis of evaluate study2019

    • Author(s)
      Nishimoto Mitsuhiro、Ohtsu Hiroshi、Marumo Takeshi、Kawarazaki Wakako、Ayuzawa Nobuhiro、Ueda Kohei、Hirohama Daigoro、Kawakami-Mori Fumiko、Shibata Shigeru、Nagase Miki、Isshiki Masashi、Oba Shigeyoshi、Shimosawa Tatsuo、Fujita Toshiro
    • Journal Title

      Hypertension Research

      Volume: 42 Issue: 4 Pages: 514

    • DOI

      10.1038/s41440-018-0201-7

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 生活習慣病の未病にかかわるエピゲノム情報2019

    • Author(s)
      丸茂丈史
    • Journal Title

      日本未病システム学会雑誌

      Volume: 25 Pages: 71-74

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells2018

    • Author(s)
      Oba Shigeyoshi、Ayuzawa Nobuhiro、Nishimoto Mitsuhiro、Kawarazaki Wakako、Ueda Kohei、Hirohama Daigoro、Kawakami-Mori Fumiko、Shimosawa Tatsuo、Marumo Takeshi、Fujita Toshiro
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 16338-16338

    • DOI

      10.1038/s41598-018-34612-3

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aberrant DNA methylation of hypothalamic angiotensin receptor in prenatal programmed hypertension2018

    • Author(s)
      Kawakami-Mori Fumiko、Nishimoto Mitsuhiro、Reheman Latapati、Kawarazaki Wakako、Ayuzawa Nobuhiro、Ueda Kohei、Hirohama Daigoro、Kohno Daisuke、Oba Shigeyoshi、Shimosawa Tatsuo、Marumo Takeshi、Fujita Toshiro
    • Journal Title

      JCI Insight

      Volume: 3 Issue: 21 Pages: 95625-95625

    • DOI

      10.1172/jci.insight.95625

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Epigenetic mechanisms involved in chronic kidney disease and the anticipated clinical applications.2019

    • Author(s)
      Takeshi Marumo.
    • Organizer
      LSBM Symposium
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 慢性腎臓病に関わるエピジェネティクスと臨床応用への展望2019

    • Author(s)
      丸茂丈史
    • Organizer
      第62回日本腎臓学会学術総会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Homer Smith Award Lecture, ‘Salt, Hypertension and the Kidneys’, American Society of Nephrology,2019

    • Author(s)
      Toshiro Fujita.
    • Organizer
      American Society of Nephrology, Kidney Week 2019, Washington, DC.
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] "Urinary kidney-specific DNA methylation signature correlates with renal function decline in diabetes"2019

    • Author(s)
      Takeshi Marumo, Daigoro Hirohama, Mitsuhiro Nishimoto, Nobuhiro Ayuzawa, Wakako Kawarazaki, Shigeyoshi Oba, Toshiro Fujita.
    • Organizer
      American Society of Nephrology, Kidney Week 2019, Washington, DC.
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] "The mineralocorticoid receptor antagonist Finerenone limits podocyte injury in high-salt loaded db/db mice"2019

    • Author(s)
      Daigoro Hirohama, Mitsuhiro Nishimoto, Nobuhiro Ayuzawa, Wakako Kawarazaki, Shigeyoshi Oba, Takeshi Marumo, Toshiro Fujita.
    • Organizer
      American Society of Nephrology, Kidney Week 2019, Washington, DC.
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Importance of dietary salt intake for the efficacy of mineralocorticoid receptor blockade against ACEI/ARB-resistant albuminuria: -a sub-analysis of EVALUATE study-.2019

    • Author(s)
      Mitsuhiro Nishimoto, Hiroshi Ohtsu, Takeshi Marumo, Wakako Kawarazaki, Nobuhiro Ayuzawa, Daigoro Hirohama, Toshiro Fujita.
    • Organizer
      International Symposium of Aldosterone and Related Substances in Hypertension 2019, Sendai
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Two different mechanism of pendrin regulation by mineralocorticoid receptor in distal nephron.2019

    • Author(s)
      Nobuhiro Ayuzawa, Mitsuhiro Nishimoto, Daigoro Hirohama, Wakako Kawarazaki, Takeshi Marumo, Toshiro Fujita.
    • Organizer
      International Symposium of Aldosterone and Related Substances in Hypertension 2019, Sendai
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 「老化に伴う食塩感受性高血圧発症機序の解明」2019

    • Author(s)
      河原崎和歌子, 水野理介, 西本光宏, 鮎澤信宏, 広浜大五郎, 森典子, 大庭成喜, 丸茂丈史, 藤田敏郎.
    • Organizer
      第62回日本腎臓学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 「ミネラロコルチコイド過剰による食塩感受性高血圧におけるPendrin活性化機構」2019

    • Author(s)
      鮎澤 信宏、広浜 大五郎、西本 光宏、河原崎 和歌子、丸茂 丈史、藤田 敏郎.
    • Organizer
      第62回日本腎臓学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 「加齢に伴う食塩感受性高血圧発症機序の解明」2019

    • Author(s)
      河原崎和歌子, 水野理介, 西本光宏, 鮎澤信宏, 広浜大五郎, 大庭成喜, 丸茂丈史, 藤田敏郎.
    • Organizer
      第42回日本高血圧学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 「エピジェネティック尿検査による糖尿病性腎症悪化の診断」2019

    • Author(s)
      丸茂丈史、星野純一、河原崎和歌子、西本光宏、鮎澤信宏、広浜大五郎、佐藤敦久、乳原善文、下澤達雄、藤田敏郎.
    • Organizer
      第42回日本高血圧学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 「加齢に伴う食塩感受性高血圧発症機序の解明」2019

    • Author(s)
      河原崎和歌子, 水野理介, 西本光宏, 鮎澤信宏, 広浜大五郎, 大庭成喜, 丸茂丈史, 藤田敏郎.
    • Organizer
      第29回日本循環薬理学会・第55回高血圧関連疾患モデル学会合同学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Two distinct regulations of pendrin by mineralocorticoid receptor in distal nephron2019

    • Author(s)
      Nobuhiro Ayuzawa, Mitsuhiro Nishimoto, Daigoro Hirohama, Wakako Kawarazaki, Takeshi Marumo, Toshiro Fujita
    • Organizer
      The 44th International Aldosterone Conference
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 糖尿病性腎症とエピゲノム あらたなバイオマーカーとなりうるか?2018

    • Author(s)
      丸茂丈史
    • Organizer
      第25回日本未病システム学会学術総会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] エピゲノム情報に基づく新しい腎臓病治療2018

    • Author(s)
      藤田敏郎、丸茂丈史
    • Organizer
      第61回日本腎臓学会学術総会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 腎臓特異的DNAメチル化を尿中マーカーとした糖尿病性腎症の尿細管障害診断法2018

    • Author(s)
      丸茂丈史、下澤達雄、河原崎和歌子、西本光宏、鮎澤信宏、広浜大五郎、上田浩平、佐藤敦久、渥美義仁、星野純一、乳原善文、藤田敏郎
    • Organizer
      第61回日本腎臓学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] RAAS-driven pendrin regulation to maintain fluid homeostasis2018

    • Author(s)
      Nobuhiro Ayuzawa, Mitsuhiro Nishimoto, Daigoro Hirohama, Kohei Ueda, Wakako Kawarazaki, Tastuo Shimosawa, Takeshi Marumo, Toshiro Fujita
    • Organizer
      第61回日本腎臓学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 加齢に伴う食塩感受性高血圧発症機序の検討2018

    • Author(s)
      河原崎和歌子、水野理介、西本光宏、鮎澤信宏、広浜大五郎、上田浩平、丸茂丈史、藤田敏郎
    • Organizer
      第61回日本腎臓学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Pendrinの血圧・水電解質代謝調節作用に関する検討2018

    • Author(s)
      広浜 大五郎、鮎澤 信宏、上田 浩平、西本 光宏、河原崎 和歌子、下澤 達雄、丸茂 丈史、柴田 茂、藤田 敏郎
    • Organizer
      第22回日本心血管内分泌代謝学会
    • Related Report
      2018 Research-status Report
  • [Presentation] Pendrinの血圧・電解質代謝調節作用に関する役割2018

    • Author(s)
      広浜 大五郎, 鮎澤 信宏, 西本 光宏, 河原崎 和歌子, 下澤 達雄, 丸茂 丈史, 柴田 茂, 藤田 敏郎
    • Organizer
      第41回日本高血圧学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 加齢に伴う食塩感受性高血圧発症におけるKlotho-Wnt-Rho pathwayの関与2018

    • Author(s)
      河原崎和歌子、水野理介、西本光宏、鮎澤信宏、広浜大五郎、森典子、大庭成喜、丸茂丈史、藤田敏郎
    • Organizer
      第41回日本高血圧学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 食塩と高血圧研究の進歩~エピジェネティクス~2018

    • Author(s)
      藤田敏郎
    • Organizer
      第41回日本高血圧学会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Remarks] 「尿への食塩排泄量を調節するPendrinにより 治療に抵抗性の高血圧が起こる仕組みを解明」

    • URL

      https://www.rcast.u-tokyo.ac.jp/ja/news/release/20200208.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] 西本光宏特任助教を筆頭著者とする論文がHypertension Research Award を受賞

    • URL

      https://www.rcast.u-tokyo.ac.jp/ja/news/report/191025.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] 「Splendid basic Hypertension Research Award」を受賞

    • URL

      https://www.rcast.u-tokyo.ac.jp/ja/news/report/191101.html

    • Related Report
      2019 Annual Research Report

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Published: 2018-07-25   Modified: 2021-02-19  

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