Development of a novel therapy for kidney diseases targeting the hypoxia sensor PHD in macrophages

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08711
• 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: Kyorin University
• Principal Investigator: Kawakami Takahisa 杏林大学, 医学部, 講師 (10722093)
• Co-Investigator(Kenkyū-buntansha): 要 伸也 杏林大学, 医学部, 教授 (60224581)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: PHD / マクロファージ / 敗血症

Outline of Final Research Achievements

Several models of inflammatory diseases were made by using macrophage(MP)-specific
PHD knockout mice (cKO) and siblings as the control to investigate the effects which the hypoxia sensor, PHD, in macrophages has on kidney diseases and inflammation. While no significant difference was observed in acute kidney injury and chronic kidney disease models, survival of cKO was significantly ameliorated in the systemic inflammation model treated with intraperitoneal injection of LPS. The analysis of blood, tissues, bone-marrow-derived MPs, and transcriptome of isolated MPs of liver showed that MPs in cKO had less pro-inflammatory tendency, which causes the longer survival. These results suggest PHD inhibition may be applied to clinical therapy for inflammatory diseases, including sepsis.

Free Research Field

腎臓病学，自然免疫

Academic Significance and Societal Importance of the Research Achievements

血中に細菌が入ることで起こる敗血症は，重度の炎症が起こることで腎臓を含む多くの臓器が障害される重症の疾患である．本研究は，白血球の一種で炎症を司るマクロファージのPHDというタンパクのはたらきを抑えることで，炎症が軽くなり，敗血症のモデルマウスの生存率を改善させることができることを示した．PHDを阻害する薬は，別の目的で既に上市されており，それらの手段によるマクロファージのPHD阻害が，敗血症や，さらには他の炎症性疾患についても臨床応用できる可能性がある．