| Project/Area Number |
16K09640
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Horita Shoko 東京大学, 医学部附属病院, 助教 (20534895)
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| Co-Investigator(Kenkyū-buntansha) |
中村 元信 東京大学, 医学部附属病院, 助教 (40459524)
山崎 修 帝京大学, 医学部, 講師 (80757229)
鈴木 正志 東京学芸大学, 保健管理センター, 教授 (90595662)
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| Research Collaborator |
Ando Hideaki
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 近位尿細管 / ナトリウム輸送 / 高血圧 / 心不全 / WNK1 / OSR1/SPAK / NBCe1 / siRNA / ナトリウム再吸収 / WNK / Na輸送 |
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| Outline of Final Research Achievements |
In renal proximal tubules (PTs) insulin (Ins) stimulates both apical NHE3 and basolateral NBCe1 via PI3K/Akt signaling, so does thiazolidinedione (TZD) via PPARg/ERK signaling; also AngII via NO/ERK signaling in human. However, the coordination mechanism regulating PT Na transport was poorly understood. We studied the role of WNK1/OSR1 pathway.
In freshly-isolated rat and human PTs, Ins and TZD markedly stimulated both NHE3 and NBCe1 activities, which was totally suppressed by OSR1/SPAK inhibitor, Closantel. Closantel also totally suppressed the AngII-stimulated NBCe1 and NHE3 activities in human PTs. Immunostaining confirmed these results. In overnight incubated rat PTs, siRNA against WNK1 but not WNK3 abolished the stimulatory effects of TZD and ins on NBCe1, so did siRNA against OSR1 but not SPAK.
These results indicate, for the first time, that in PTs signaling cascades stimulating Na transport converge into WNK1/OSR1 pathway, which may work as a master regulator of PT Na transport.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究にて，これまで不明であった近位尿細管Na輸送の異なる刺激要素（インスリン，チアゾリジン，アンジオテンシンII）を，WNK1/OSR1が収斂し，WNK1/OSR1がこの輸送のmaster regulatorであることが初めて示された。すなわち，Na過剰貯留による高血圧，心不全等の治療のターゲットにWNK1/OSR1がなりえることが示唆され，新規治療薬開発においても有力な候補となることが期待される。
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