Investigation of the role of NFAT5 in the regulation of renal interstitial microenviroment and blood pressure

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08280
• 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: Kumamoto University
• Principal Investigator: Izumi Yuichiro 熊本大学, 病院, 特任准教授 (20736243)
• Co-Investigator(Kenkyū-buntansha): 向山 政志 熊本大学, 大学院生命科学研究部(医), 教授 (40270558)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 食塩感受性高血圧 / NFAT5 / 上皮型ナトリウムチャネル

Outline of Final Research Achievements

Blood pressure and water and electrolyte metabolism of drug-inducible and renal tubular cell-specific NFAT5 (nuclear activated T-cells 5) KO mice were examined by telemetry method and measurement of urine and blood parameters. The effects of high-salt diet and sodium channel inhibitor on the blood pressure and water and electrolyte metabolism were examined.
The results indicated that the KO mice exhibit salt-sensitive hypertension which is accompanied by the over expression of epithelium sodium channel (ENaC). The activation of immune responses and excessive interstitial osmolality caused by the accumulation of sodium in the renal medulla were observed. In contrast, the interstitial urea level was significantly decreased. We hypothesize that the deficit of NFAT5 in renal tubular cells induces a change of interstitial microenvironment followed by the activation of immune responses, resulting in salt-sensitive hypertension.

Free Research Field

腎臓内科学

Academic Significance and Societal Importance of the Research Achievements

本研究は、ゲノム関連解析で示唆されているヒトの血圧高値と血清ナトリウム濃度高値へのNFAT5の関連を、尿細管細胞特異的NFAT5欠損（KO）マウスを用いて実証したものである。本研究により、正常な水・電解質代謝に必須の腎臓の尿細管細胞において、NFAT5の機能異常が食塩感受性高血圧を呈し、さらにヒトの食塩感受性高血圧の原因と一つとされる上皮型ナトリウム（Na）チャネル（ENaC）を介した尿中Na再吸収亢進と腎組織内の免疫応答の異常を合併することが明らかになった。NFAT5 KOマウスのさらに詳細な解析を進めることで、食塩感受性高血圧の発症・進展機序の解明とその治療法の開発が大いに期待できる。