Elucidation of the Mechanism of Age-Related Salt-Sensitive Hypertension and Novel Therapeutic Strategies

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08028
• 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: The University of Tokyo
• Principal Investigator: Kawarazaki Wakako 東京大学, 先端科学技術研究センター, 特任准教授 (50424594)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 加齢 / 食塩感受性 / 高血圧 / Wnt / Rho / Klotho

Outline of Final Research Achievements

It has been known from epidemiological studies that both the incidence of hypertension and salt sensitivity increase with age, but their mechanisms have been unclear. Using aged mice, we clarified the mechanism by which excessive salt intake in the presence of decreased Klotho in the blood causes activation of the Wnt5a-RhoA system in the vasoconstrictor pathway, resulting in increased vasoconstrictor response and development of hypertension. In addition, we showed that age-related hypertension was significantly suppressed by Klotho supplementation, Wnt inhibitors, and Rho kinase inhibitors. This study provides a novel therapeutic strategy for hypertension in the elderly and emphasizes the importance of salt reduction.

Free Research Field

腎臓内科学

Academic Significance and Societal Importance of the Research Achievements

学術的意義としては、Wnt non-canonical経路が加齢現象や高血圧発症に関わる事、重要な血管収縮物質であるアンジオテンシンⅡ(AngⅡ)による血管収縮にはWnt5aが必要でありWnt5a-RhoA経路の活性化を介して生じ、Klothoにより抑制されることを初めて明らかにした。また、高齢マウスの腎動脈ではAngⅡへの感受性が増大しており、食塩摂取時にWnt-RhoA経路活性化による血管収縮性の増強が腎動脈で生じ、腎血流が低下して高血圧を発症する機序を証明し、Klotho補充にて正常化することを示した。また社会に高齢者高血圧の新規治療法を提示するとともに、減塩の重要性を発信した。