Regulation Mechanism of blood pressure through analysis of KLHL2/3 in vivo

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K16076
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ZENIYA Moko (三澤) 東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (10760283)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 高血圧 / KLHL3 / KLHL2 / ナトリウム輸送体 / 塩分感受性

Outline of Final Research Achievements

WNK-OSR1/SPAK-NCC phosphorylation cascade is involved in salt-sensitive hypertension through regulation of renal sodium excretion and vasoconstriction. WNK kinases are mediated by KLHL2 and KLHL3, however, the detailed mechanism remained unknown. In this study, we generated KLHL2 knock-out (KO) and KLHL3 KO mice and analyzed their phenotypes. As a result, we elucidated the localization in vivo of KLHL2 and KLHL3, involvement of KLHL2 and KLHL3 in salt-sensitive hypertension, and the pathophysiological roles of KLHL2 and KLHL3 for the regulation of WNK-OSR1/SPAK-NCC cascade.
In addition, we also clarified that the WNK cascade is upregulated in salt-sensitive hypertension observed in chronic kidney disease (CKD). Proteasome inhibitor bortezomib were identified as a novel therapeutic candidate for fibrosis in CKD.

Free Research Field

腎臓内科学

Academic Significance and Societal Importance of the Research Achievements

高血圧患者は日本に1000万人以上存在し、中でも塩分感受性高血圧は臓器障害を起こしやすく、その対策は大変重要な課題である。今回我々が一連の研究により、KLHL3及びKLHL2の生体・特に腎臓における機能を解明したことで、WNK-OSR1/SPAK-NCCカスケードの上位調節機構について、より詳細な仕組みが明らかになった。このことは、塩分感受性高血圧の今後の病態全容解明や治療法開発に向けた学術的・社会的前進であると考えている。