Elucidation of the functional significance of vascular endothelial dysfunction in VEGF inhibitors-induced nephropathy

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15300
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Iwate Medical University
• Principal Investigator: Nihei Satoru 岩手医科大学, 薬学部, 研究員 (30898888)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: VEGF阻害薬 / 血管内皮機能障害 / 腎障害 / 蛋白尿 / 高血圧 / エンドセリン-1（ET-1） / ベバシズマブ

Outline of Final Research Achievements

In this study, we aimed to show the functional significance of vascular endothelial dysfunction in vascular endothelial growth factor (VEGF) inhibitors-induced nephrotoxicity. An in vitro model of cultured human glomerular endothelial cells showed that endothelin-1 (ET-1), a marker of vascular endothelial dysfunction, was upregulated by treatment with a humanized anti-VEGF monoclonal antibody (bevacizumab). In the study for patients treated with bevacizumab, we identified that plasma ET-1 levels were associated with the development of nephrotoxicity during bevacizumab treatment. Furthermore, the association between vascular endothelial function and nephrotoxicity was supported by the results of reactive hyperemia index (RHI), a measure of vascular endothelial function. We discovered that vascular endothelial dysfunction is involved in the pathogenesis of VEGF inhibitors-induced nephrotoxicity.

Free Research Field

医療系薬学

Academic Significance and Societal Importance of the Research Achievements

ベバシズマブなどのVEGF阻害薬は種々のがん疾患に対するキードラッグとして重要な役割を担っているが、蛋白尿や高血圧による腎障害が用量制限毒性となり、投与の中断や減量の原因となる。高血圧は降圧薬の使用によりコントロール可能なことが多いが、蛋白尿に対しては有効な予防法や治療法は存在しない。したがって、腎障害を回避するための新たな治療ターゲットやバイオマーカーの知見が求められており、本研究の成果はVEGF阻害薬に伴う血管内皮機能障害の機能的意義を明らかにするものであり、新規概念を提示するとともに臨床応用の可能性が高いと考える。