Investigation of effectiveness of Aryl hydrocarbon receptor blockade on cardiorenal syndrome

• Project/Area Number: 18K08050
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Toho University
• Principal Investigator: Morita Toshisuke 東邦大学, 医学部, 教授 (60286094)
• Project Period (FY): 2018-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 心腎連関 / インドキシル硫酸 / 芳香族炭化水素受容体 / ケルセチン

Outline of Final Research Achievements

In this study, the effects of various polyphenols on indoxyl sulfate (IS)-induced endothelial cell injury were investigated in human aortic endothelial cells. Quercetin suppressed the activation of the IS-Aryl hydrocarbon receptor (AhR) pathway and reduced the secretion of MCP-1. Based on these findings, IS-treated 5/6 nephrectomized mice with renal failure were created to investigate the effect of quercetin administration on the cardiovascular system in the IS-administered group. Our results demonstrated that quercetin protected against aortic injury mediated by IS-induced AhR activation, and inhibited the progression of myocardial fibrosis and cardiac diastolic dysfunction.

Academic Significance and Societal Importance of the Research Achievements

ISの血中濃度は慢性腎臓病のステージ進行とともに上昇するが、血中ではISの90％以上がアルブミンと結合しており、現在でも血液透析での除去は困難である。また、慢性腎臓病に対する薬剤であるAST-120は、その副作用等により服薬アドヒアランスが悪い。今回の研究から、食品由来のケルセチンがIS-AhR経路遮断による心腎連関抑制に有効である可能性が示唆された。これらの結果は、ISの作用点をターゲットとした慢性腎臓病患者の心血管病の発症進展を抑制する新しい治療手段に繋がるものと考えられる。