Cytotoxicity of chromatin from macrophages in rhabdomyolysis-induced acute kidney injury

• Project/Area Number: 16K19497
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Keio University
• Principal Investigator: Okubo Koshu 慶應義塾大学, 医学部(信濃町), 共同研究員 (60749125)
• Research Collaborator: KUROSAWA Miho ; URANO Yasuteru
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 横紋筋融解症 / 急性腎障害 / 白血球細胞外トラップ / Mac-1

Outline of Final Research Achievements

Rhabdomyolysis is a serious syndrome caused by skeletal muscle injury and the subsequent release of breakdown products from damaged muscle cells into systemic circulation. The muscle damage can lead to acute kidney injury (AKI).Recently, macrophages were implicated in the disease pathogenesis of rhabdomyolysis-induced AKI, but the precise molecular mechanism remains unclear. In the present study, we show that macrophages released extracellular traps (ETs) comprising DNA fibers and granule proteins in a mouse model of rhabdomyolysis. Heme-activated platelets released from necrotic muscle cells during rhabdomyolysis enhanced the production of macrophage extracellular traps (METs). Here we report, this unanticipated role for METs and platelets as a sensor of myoglobin-derived heme in rhabdomyolysis-induced AKI. Also, we found a new therapeutic tool for prevention of AKI after rhabdomyolysis, which might rescue some sufferers of this pathology.

Research Products

• [Journal Article] Macrophage extracellular trap formation promoted by platelet activation is a key mediator of rhabdomyolysis-induced acute kidney injury (2018)
  • Author(s): Okubo K, Kurosawa M, Kamiya M, Urano Y, Suzuki A, Yamamoto K, Hase K, Homma K, Sasaki J, Miyauchi H, Hoshino T, Hayashi M, Mayadas TN, Hirahashi J.
  • Journal Title: Nature medicine Volume: 24 Pages: 232-238
  • DOI: 10.1038/nm.4462
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Macrophage extracellular traps induced by Mac-1 (CD11b/CD18) dependent platelet-macrophage interactions progress acute kidney injury (2017)
  • Author(s): Koshu Okubo
  • Organizer: The 18th International Vasculitis and ANCA Workshop
  • Place of Presentation: 伊藤国際学術研究センター （東京都文京区）
  • Year and Date: 2017-03-27
  • Int'l Joint Research
• [Presentation] Macrophage Extracellular Traps Induced by Mac-1 (CD11b/CD18) Dependent Platelet-Macrophage Interactions Promotes Acute Kidney Injury in Rhabdomyolysis (2016)
  • Author(s): Koshu Okubo
  • Organizer: ASN Kidney Week 2016 (American Society of Nephrology)
  • Place of Presentation: シカゴ(米国）
  • Year and Date: 2016-11-17
  • Int'l Joint Research
• [Presentation] 好中球細胞外トラップ形成における活性酸素認識プローブを用いた新規イメージング技術の応用 (2016)
  • Author(s): 大久保光修
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市
  • Year and Date: 2016-09-27
  • Invited