Study on mechanisms of exacerbation of tissue fibrogenesis by NOX4-derived reactive oxygen species

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07326
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Katsuyama Masato 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (60315934)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 活性酸素種 / NADPHオキシダーゼ / 組織線維化

Outline of Final Research Achievements

It is well known that NOX4/NADPH oxidase is induced at mRNA levels by TGF-β and is involved in fibrogenesis. In human lung fibroblasts transfected with siRNAs against NOX4, levels of endoglin, a co-receptor of TGF-β receptor, were decreased at protein levels compared with those in control siRNA-transfected cells. Smad binding element-dependent transcriptional activation by TGF-β was suppressed by RNA interference against NOX4. These results suggest that feedforward regulations to exacerbate tissue fibrogenesis exist between NOX4 and endoglin of which functional expression seems to be maintained by NOX4-derived reactive oxygen species.

Free Research Field

薬理学、分子生物学

Academic Significance and Societal Importance of the Research Achievements

組織線維化は不可逆的な変化であり、根治可能な薬物療法は現在のところ存在しない。NOX4は活性酸素種（ROS）を産生するNADPHオキシダーゼの触媒サブユニットの一分子種であり、NOX4が産生するROSは組織線維化に重要な役割を果たすが、その分子機構は未解明の点が多い。本研究では「TGF-β→NOX4の発現誘導→エンドグリンの機能的発現維持→TGF-βシグナルの増強」という線維化増悪サイクルの存在が示唆された。新たな抗線維化薬の開発のための基礎的知見となるものと考えている。