Exploring the new role of GABA on water diuresis and renal protection

Research Project

Project/Area Number	16K09658
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Kidney internal medicine
Research Institution	Tokyo Women's Medical University
Principal Investigator	Yatabe Junichi 東京女子医科大学, 医学部, 講師 (10566681)
Project Period (FY)	2016-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000) Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000) Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000) Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords	高血圧 / GABA / リジン / アクアポリン / ドーパミン / GRK4 / 利尿 / 高血圧症
Outline of Final Research Achievements	Dopamine acts on renal tubular dopamine D1 receptor (D1R) to induce natriuresis. When D1R is phosphorylated by GRK4, the receptor is desensitized, and urinary sodium excretion is decreased. Meanwhile, it was reported that GRK4 in the central nervous system also desensitizes GABA-B receptor R2 subtype, suggesting the possibility that GRK4 is additionally involved in the natriuretic actions of GABA. We analyzed renal expression of GABA receptors and found that GABA- R2 is expressed mainly in principal cells of collecting ducts. Also, we found that blood and urine concentrations of lysine were reduced in hypertensive model rats. Lysine is metabolized to pipecolic acid, which modulates GABA signaling. Our findings revealed possible mechanism of relations between hypertension and GABA.
Academic Significance and Societal Importance of the Research Achievements	GABAによる利尿作用の詳細が明らかとなれば、尿酸上昇などの副作用が少ない新しい降圧利尿薬の開発を促す可能性もある。本研究では、GABA受容体に作用するリジンとその代謝物ピペコリン酸に着目することとなったが、GABA受容体の脱感作を司るGRK4の遺伝子多型とAQP2の相互作用が明らかになれば、高血圧症の個別化医療を実現するために重要な知見を与えることになる。