Double-strand DNA injury in acute and chronic stages of renal allografts

• Project/Area Number: 18K08256
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Kanazawa Medical University
• Principal Investigator: YOKOYAMA Hitoshi 金沢医科大学, 医学部, 教授 (50191531)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 疾患コホート / DNA損傷マーカー / VI型膠原線維 / 移植腎障害 / 移植腎 / DNA損傷

Outline of Final Research Achievements

It has been clarified the relation between the DNA damage at the early phase after renal transplantation and the primary non-functioning or delayed graft function of transplant kidneys in the cohort of renal transplantation (137 cases). The quantitative evaluation of DNA damage is an appropriate index for the diagnosis of the onset of renal dysfunction from the early to the late stages of transplanted renal allografts.
Collagen type VI (COL6) deposition occurs in various glomerular diseases such as transplanted nephropathy, causing serious pathological damage like nodular lesions. In in vitro studies, COL6 secretion from human renal glomerular endothelial cells (HRGECs) was induced by Mitomycin C (MMc) treatment associated with the number of γ-H2AX-positive cells. These results confirm that nodular glomerulosclerosis partially results from DNA damage in the glomerulus and that DNA damage induced COL6 secretion from HRGECs occurs through an ATR and ANXA2-mediated pathway.

Academic Significance and Societal Importance of the Research Achievements

本研究により，臨床的に問題となっている急性期から慢性期に至る一連の移植腎障害の進展における二重鎖DNA損傷からⅥ型膠原線維蓄積による糸球体硬化に至る機序を解明し，その分子メカニズムに対する新しい治療法の開発への道を開き，末期腎不全への進行抑制と腎不全対策としての次世代移植医療への貢献が期待される．

Research Products

• [Journal Article] Changes in double-strand DNA breaks predict delayed graft function (DGF) in Japanese renal allograft recipients. (2020)
  • Author(s): Okada K, Nomura-Nakayama K, Okushi Y, Okino K, Mukai K, Hayashi N, Fujimoto K, Adachi H, Yokoyama H.
  • Journal Title: Clinical and Experimental Nephrology Volume: 24 Issue: 1 Pages: 96104-96104
  • DOI: 10.1007/s10157-019-01793-8
  • Peer Reviewed
• [Journal Article] DNA damage in human glomerular endothelial cells induces nodular glomerulosclerosis via an ATR and ANXA2 pathway (2020)
  • Author(s): Ai Fujii, Yumi Sunatani, Kengo Furuichi, Keiji Fujimoto, Hiroki Adachi, Kuniyoshi Iwabuchi, Hitoshi Yokoyama
  • Journal Title: Scientific Reports Volume: 22 Issue: 1 Pages: 22206-22206
  • DOI: 10.1038/s41598-020-79106-3
  • Peer Reviewed / Open Access
• [Presentation] Double-strand DNA (dsDNA) damage in human glomerular endothelial cells induces collagen type VI secretion via an ATR and ANXA2 pathway (2021)
  • Author(s): Ai Fujii, Yumi Sunatani, Kengo Furuichi, Keiji Fujimoto, Hiroki Adachi, Kuniyoshi Iwabuchi, Hitoshi Yokoyama
  • Organizer: The 10th CKD Frontier Meeting
  • Int'l Joint Research
• [Presentation] DNA double-strand breaks of human glomerular endothelial cells induced collagen type VI excretion and nodular lesions in various kidney diseases (2020)
  • Author(s): Ai Fujii, Yumi Sunatani, Kengo Furuichi, Keiji Fujimoto, Hiroki Adachi, Kuniyoshi Iwabuchi, Hitoshi Yokoyama
  • Organizer: The Annual meeting of the American Society of Nephrology.
  • Int'l Joint Research
• [Presentation] DNA damage in human glomerular endothelial cells induce nodular glomerulosclerosis via ATR pathways (2020)
  • Author(s): Ai Fujii, Yumi Sunatani, Kengo Furuichi, Keiji Fujimoto, Hiroki Adachi, Kuniyoshi Iwabuchi, Hitoshi Yokoyama
  • Organizer: 9th CKD Frontier, Nagoya
  • Int'l Joint Research
• [Presentation] ネフローゼ症候群:腎疾患の腎組織所見と新しい免疫抑制療法 (2019)
  • Author(s): 横山仁
  • Organizer: 日本内科学会講演会
  • Invited
• [Presentation] Changes in double-strand DNA breaks predict delayed graft function (DGF) in Japanese renal allograft recipient (2019)
  • Author(s): Keiichiro Okada, Hitoshi Yokoyama
  • Organizer: 56th ERA-EDTA Congress in Budapest
  • Int'l Joint Research
• [Presentation] 二重鎖DNA損傷と移植腎機能発現に関する検討 (2018)
  • Author(s): 岡田圭一郎，矢部友久，藤井愛，野村佳苗，大串勇気，沖野一晃，向井清孝，藤本圭司，足立浩樹，横山仁
  • Organizer: 日本腎臓学会