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Elucidation of the role of epigenetics in abnormalities in NAD synthesis leading to kidney damage

Research Project

Project/Area Number 21K08261
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53040:Nephrology-related
Research InstitutionIwate Medical University (2022-2023)
International University of Health and Welfare (2021)

Principal Investigator

Hasan Arif Ul  岩手医科大学, 医学部, 講師 (00570368)

Co-Investigator(Kenkyū-buntansha) 丸茂 丈史  国際医療福祉大学, 医学部, 教授 (70265817)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsNAD合成 / エピジェネティクス / 急性腎障害 / 糖尿病性腎症 / 低酸素症
Outline of Research at the Start

急性腎障害(acute kidney injury:AKI)は死亡率が高いうえ、慢性腎臓病(chronic kidney disease: CKD)の原因になる。しかし、AKIの成立メカニズムには不明な部分が多く残されており、解明すれば新たな治療標的になる。最近AKIへのNAD合成系低下の関与が示され低酸素がNAD系の合成を阻害することが明らかになったが、その調節機構はいまだ不明である。申請者らはNAD合成系へのエピジェネティクス機構の関与を検討する。

Outline of Final Research Achievements

This study was conducted to investigate the role of epigenetics on NAD synthesis in acute kidney injury and chronic kidney disease caused by diabetes. Single-nuclear RNA sequencing data available in public database from kidneys collected from healthy subjects and diabetic patients revealed that genes related to the NAD synthesis pathway were dysregulated in the kidneys of patients with acute kidney injury and diabetic chronic kidney disease. Using human renal epithelial cells, inhibitors of histone deacetylation and histone demethylation increased NAD production by upregulating the expression of several genes related to NAD synthesis. Furthermore, these interventions reduced the expression of markers of kidney injury. These results suggest that inhibitors of the histone system may improve kidney injury.

Academic Significance and Societal Importance of the Research Achievements

急性腎障害は死亡率が高いうえ、慢性腎臓病の原因になる。しかし、急性腎障害の成立メカニズムには不明な部分が多く残されており、解明すれば新たな治療標的になる。一方、糖尿病性腎症は慢性腎臓病の主要疾患である。近年の研究で、NADの投与により腎障害が回復することが証明されたが、その機能はまだ不明である。がんではエピジェネティクス異常を標的とした診断・治療が臨床応用されているが、生活習慣病でもエピジェネティック異常の病的意義が次第に解明され診断・治療の標的として注目されている。本研究により結果は腎障害に起きるNAD合成の異常に関わる鍵となり、エピジェネティック修飾は新たな治療方法の可能性が考えられる。

Report

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

    (7 results)

All 2024 2023 2022 2021

All Journal Article (2 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (5 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] CD146/MCAM links doxorubicin-induced epigenetic dysregulation to the impaired fatty acid transportation in H9c2 cardiomyoblasts2024

    • Author(s)
      Hasan Arif Ul、Obara Mami、Sato Sachiko、Kondo Yukiko、Taira Eiichi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 693 Pages: 149370-149370

    • DOI

      10.1016/j.bbrc.2023.149370

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Klotho supplementation reverses renal dysfunction and interstitial fibrosis in remnant kidney.2023

    • Author(s)
      Takenaka Tsuneo、Hasan Arif、Marumo Takeshi、Inoue Tsutomu、Miyazaki Takashi、Suzuki Hiromichi、Kurosaki Yoshifumi、Ishii Naohito、Nishiyama Akira、Hayashi Matsuhiko
    • Journal Title

      Kidney and Blood Pressure Research

      Volume: 1 Issue: 1 Pages: 1-1

    • DOI

      10.1159/000530469

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Epigenetic regulation of CD146/MCAM ameliorates doxorubicin-induced dysregulation of Fabp4 on H9c2 cardiomyoblasts2023

    • Author(s)
      Hasan Arif Ul, Obara Mami, Sato Sachiko, Kondo Yukiko, Taira Eiichi
    • Organizer
      第74回日本薬理学会北部会
    • Related Report
      2023 Annual Research Report
  • [Presentation] KDM4阻害剤であるNCG00244536はB16メラノーマ細胞の増殖を抑制する2023

    • Author(s)
      平田 翔、長瀬 由佳子、ハサン アリフ ウル、佐藤 幸子、小原 真美、近藤 ゆき子、 平 英一
    • Organizer
      第74回日本薬理学会北部会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Inhibition of histone demethylation augments NAD synthesis through the Preiss-Handle rpathway in cultured human proximal tubular epithelial cell line2022

    • Author(s)
      ハサン アリフ ウル 、丸茂 丈史、小原 真美 、佐藤 幸子 、近藤 ゆき子 、村瀬 真ー 、平 英一
    • Organizer
      The 96th Annual Meeting of the Japanese Pharmacological Society
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Dietary sucrose-mediated inhibition of pyroptosis in intestinal epithelial cells precipitates obesity2022

    • Author(s)
      佐藤 幸子 、ハサン アリフ ウル 、小原 真美 、平 英一
    • Organizer
      The 100th Anniversary Annual Meeting of The Physiological Society of Japan
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] HDAC inhibitors augment de novo NAD synthesis in renal proximal epithelial cells2021

    • Author(s)
      ハサン アリフ ウル 、三宅克也、村瀬真ー、丸茂 丈史
    • Organizer
      11th Academic Conference of International University of Health and Welfare University Conference, 2021, Tokyo, Japan
    • Related Report
      2021 Research-status Report

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

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