| Project/Area Number |
24790836
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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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 東京医科歯科大学, 医学部附属病院, 講師 (90510355)
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| Project Period (FY) |
2012-04-01 – 2014-03-31
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| Project Status |
Completed (Fiscal Year 2013)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | インスリン / メタボリック症候群 / 塩分感受性高血圧 / WNKキナーゼ / サイアザイド / 水・電解質代謝学 / 肥満 / WNKシグナル / WNK / NCC / 高血圧 |
|---|
| Research Abstract |
We found renal WNK-OSR1/SPAK-NCC cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. In SPAK/OSR1 knock-in db/db mice, increased phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and phosphorylation of NCC. Moreover, we found that Increased NCC phosphorylation is regulated by the PI3K/Akt signaling cascade in the kidney in response to hyperinsulinemia. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome. We also found that increased protein expression levels of WNK1 and WNK4 kinases cause PHAII by KLHL3 mutation, due to impaired KLHL3-Cullin3 mediated ubiquitination.
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