| Project/Area Number |
20890062
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| Research Category |
Grant-in-Aid for Young Scientists (Start-up)
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| Allocation Type | Single-year Grants |
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| Research Field |
Kidney internal medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
SOHARA Eisei Tokyo Medical and Dental University, 医歯学総合研究科, 助教 (90510355)
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| Project Period (FY) |
2008 – 2009
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| Project Status |
Completed (Fiscal Year 2009)
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| Budget Amount *help |
¥3,302,000 (Direct Cost: ¥2,540,000、Indirect Cost: ¥762,000)
Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2008: ¥1,742,000 (Direct Cost: ¥1,340,000、Indirect Cost: ¥402,000)
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| Keywords | 塩分感受性高血圧 / インスリン / NaCl共輸送体 / WNKキナーゼ / 高血圧 / 多発性嚢胞腎 |
|---|
| Research Abstract |
The metabolic syndrome causes hyperinsulinemia and enhances salt-sensitive hypertension. However, the mechanisms responsible for the greater salt-sensitivity in hyperinsulinemic patients are still unknown. Pseudohypoaldosteronism type II (PHAII) is an autosomal dominant disease characterized by salt-sensitive hypertension due to increased sodium reabsorption in the kidney through activation of the WNK kinase-OSR1/SPAK kinase-NaCl cotransporter (NCC) phosphorylation cascade, which we recently discovered. We found that a PHAII-causing mutant WNK4 (WNK4 R1185C) abnormally increased phosphorylation of WNK4 at serine 1190, which resulted in activation of the downstream OSR1/SPAK-NCC phosphorylation cascade. Furthermore, we clarified that insulin is a powerful stimulator for WNK4 1190S phosphorylation, thereby activating the WNK-OSR1/SPAK-NCC cascade in vitro and in vivo. Thus, our results clearly show that a hyperinsulinemic condition causes salt-sensitive hypertension by the same mechanism as identified in PHAII. However, we could not find the significant relationship between PKD and WNK kinase.
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