Development of novel therapeutics for chronic and acute kidney injury through the regulation of CCN2 function

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K08731
• 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: Saitama Medical University
• Principal Investigator: Inoue Tsutomu 埼玉医科大学, 医学部, 教授 (30406475)
• Co-Investigator(Kenkyū-buntansha): 岡田 浩一 埼玉医科大学, 医学部, 教授 (60233342)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: 慢性腎臓病 / 線維化 / CCN2

Outline of Final Research Achievements

Chronic kidney disease (CKD), when it progresses, necessitates dialysis and is a risk factor for cardiovascular disease and infections, making it a significant underlying condition related to major causes of death in Japan. Currently, there are no effective means to halt the progression of CKD, and the lack of appropriate drugs for its treatment is considered a prime example of unmet medical needs. The progression of CKD is histologically characterized by kidney fibrosis. In damaged kidneys, tubular epithelial cells are known to produce CCN2, which promotes kidney fibrosis. This study elucidated the mechanism by which CCN2 phosphorylates FAK (Focal Adhesion Kinase) in tubular epithelial cells via integrins, ultimately causing β-catenin to act as a transcription factor and advance kidney fibrosis.

Free Research Field

腎臓学

Academic Significance and Societal Importance of the Research Achievements

臓器の線維化は、腎臓に限らず多数の臓器における慢性進行性の機能低下に関わる重要な病態である（例：肺線維症、皮膚硬化症、慢性心不全、肝硬変症）。その多くの病態において、CCN2が重要な液性因子であることが知られている。本研究の成果は、慢性腎臓病に限らない臓器線維化症に対する、新規治療薬開発に関わる重要な知見を提供する。さらに、本研究で腎線維化抑制効果を発揮したデコイペプチドは、CCN2-インテグリン相互作用の阻害効果を発揮することが明らかであり、同protein to protein interaction阻害薬として、具体的な慢性腎臓病治療薬のリード化合物となり得る。