Mechanism of Acute Kidney Injury Induced by Remote organ injury

• Project/Area Number: 19K21319
• Project/Area Number (Other): 18H06216 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Jichi Medical University
• Principal Investigator: Komada Takanori 自治医科大学, 医学部, 助教 (90824730)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: インフラマソーム / Absent in melanoma 2 / 二本鎖DNA / 急性腎障害 / 細胞死 / 線維化 / AIM2 / DNA / 炎症

Outline of Research at the Start

急性腎障害（AKI）は、短時間に腎機能が低下して窒素含有老廃物が貯留する重篤な病態である。肺・肝・心などの他臓器障害によってAKIが発症・増悪することが知られているが、その機序は明らかにされていない。障害臓器から放出されるDNAが、腎で危険信号として認識されて炎症を惹起し、それがAKI増悪に働く可能性が考えられる。本研究では、インフラマソームと呼ばれる自然免疫機構がDNAセンサーとして働き、AKIに寄与することを明らかにし、その制御法を開発する。

Outline of Final Research Achievements

Acute kidney injury (AKI) is known worsened under conditions of multi-organ or remote-organ failure. In this study, we examined the hypothesis that dead cell DNA derived from rhabdomyolysis reaches the kidney and influences the AKI onset through a DNA sensor, absent in melanoma 2 (AIM2). Using a rhabdomyolysis-induced AKI (RIAKI) model, we compared the pathophysiological changes under RIAKI between AIM2 knockout and wild-type mice. Dead cell DNA was involved in AKI progression, but AIM2 deficiency worsened AKI. Our results indicated that AIM2 contributed to AKI independently of the inflammasome.

Academic Significance and Societal Importance of the Research Achievements

横紋筋融解症による急性腎障害は、特異的な治療法がなく腎予後・生命予後に影響する。本研究では、壊死細胞二本鎖DNAが治療標的となりうること、また細胞質内DNAセンサーであるAIM2が病態に関与することを示した。今後詳細にその機序をあきらかにすることで、AKIの新たな治療法開発に繋がることが期待できる。

Research Products

• [Int'l Joint Research] The University of Calgary(カナダ)
• [Journal Article] GSDME-Dependent Incomplete Pyroptosis Permits Selective IL-1α Release under Caspase-1 Inhibition (2020)
  • Author(s): Aizawa Emi、Karasawa Tadayoshi、Watanabe Sachiko、Komada Takanori、Kimura Hiroaki、Kamata Ryo、Ito Homare、Hishida Erika、Yamada Naoya、Kasahara Tadashi、Mori Yoshiyuki、Takahashi Masafumi
  • Journal Title: iScience Volume: 23 Issue: 5 Pages: 101070-101070
  • DOI: 10.1016/j.isci.2020.101070
  • Peer Reviewed / Open Access
• [Journal Article] Glucose regulates hypoxia-induced NLRP3 inflammasome activation in macrophages. (2020)
  • Author(s): 1)Watanabe S, Usui-Kawanishi F, Karasawa, Kimura H, Kamata R, Inoue, Mise N, Kasahara T, Takahashi M
  • Journal Title: J Cell Physiol Volume: - Issue: 10 Pages: 7554-7566
  • DOI: 10.1002/jcp.29659
  • Peer Reviewed
• [Journal Article] Crucial role of NLRP3 inflammasome in a murine model of Kawasaki disease. (2020)
  • Author(s): 4)Anzai F, Watanabe S, Kimura H, Kamata R, Karasawa T, Komada T, Nakamura J, Nagi-Miura N, Ohno N, Takeishi Y, Takahashi M
  • Journal Title: J Mol Cell Cardiol Volume: 138 Pages: 185-196
  • DOI: 10.1016/j.yjmcc.2019.11.158
  • Peer Reviewed / Open Access
• [Journal Article] Ferroptosis driven by radical oxidation of n-6 fatty acids mediates acetaminophen-induced acute liver failure. (2020)
  • Author(s): 2)Yamada N, Karasawa T, Kimura H, Watanabe S, Komada T, Kamata R, Sampilvanjil A, Ito J, Nakagawa K, Kuwata H, Hara S, Sakuma Y, Sata N, Takahashi M
  • Journal Title: Cell Death Dis Volume: 11 Issue: 2 Pages: 144-144
  • DOI: 10.1038/s41419-020-2334-2
  • Peer Reviewed / Open Access
• [Journal Article] Cigarette smoke extract induces ferroptosis in vascular smooth muscle cells (2020)
  • Author(s): Sampilvanjil Ariunaa、Karasawa Tadayoshi、Yamada Naoya、Komada Takanori、Higashi Tsunehito、Baatarjav Chintogtokh、Watanabe Sachiko、Kamata Ryo、Ohno Nobuhiko、Takahashi Masafumi
  • Journal Title: American Journal of Physiology-Heart and Circulatory Physiology Volume: 318 Issue: 3 Pages: H508-H518
  • DOI: 10.1152/ajpheart.00559.2019
  • Peer Reviewed / Open Access
• [Journal Article] Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: potential role of ferroptosis. (2020)
  • Author(s): 3)Yamada N, Karasawa T, Wakiya T, Sadatomo A, Ito H, Kamata R, Watanabe S, Komada T, Kimura H, Sanada Y, Sakuma Y, Mizuta K, Sata N, Takahashi M
  • Journal Title: Am J Transplant Volume: - Issue: 6 Pages: 1606-1618
  • DOI: 10.1111/ajt.15773
  • Peer Reviewed / Open Access
• [Journal Article] The role of inflammasomes in kidney disease (2019)
  • Author(s): Komada Takanori、Muruve Daniel A.
  • Journal Title: Nature Reviews Nephrology Volume: 15 Issue: 8 Pages: 501-520
  • DOI: 10.1038/s41581-019-0158-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Crucial role of NLRP3 inflammasome in the development of peritoneal dialysis-related peritoneal fibrosis. (2019)
  • Author(s): 6)Hishida E, Ito H, Komada T, Karasawa T, Kimura H, Watanabe S, Kamata R, Aizawa E, Kasahara T, Morishita Y, AkimotoT, Nagata D, Takahashi M
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 10363-10363
  • DOI: 10.1038/s41598-019-46504-1
  • Peer Reviewed / Open Access
• [Journal Article] Inflammasome-independent and atypical processing of IL-1β contributes to acid aspiration-induced acute lung injury. (2019)
  • Author(s): 5)Mizushina Y, Karasawa T, Aizawa K, Kimura H, Watanabe S, Kamata R, Komada T, Mato N, Kasahara T, Koyama S, Bando M, Hagiwara K, Takahashi M
  • Journal Title: J Immunol Volume: 203 Issue: 1 Pages: 236-246
  • DOI: 10.4049/jimmunol.1900168
  • Peer Reviewed / Open Access
• [Journal Article] Role of TLR5 in inflammation and tissue damage after intestinal ischemia-reperfusion injury. (2019)
  • Author(s): 7)Ito H, Sadatomo A, Inoue Y, Yamada N, Aizawa E, Hishida E, Kamata R, Karasawa T, Kimura H, Watanabe S, Komada T, Horie H, Kitagawa J, Sata N, Takahashi M
  • Journal Title: Biochem Biophys Res Commun Volume: 519 Issue: 1 Pages: 15-22
  • DOI: 10.1016/j.bbrc.2019.08.083
  • Peer Reviewed / Open Access
• [Remarks] 自治医科大学炎症・免疫研究部ホームページ
  • URL: http://www.jichi.ac.jp/inflammation/index.html