|Budget Amount *help
¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000)
Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2011: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2010: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
The purpose of this study is to further characterize the WNK-NCC signal transduction system and to propose a novel strategy for treatment of hypertension.
Transgenic mice overexpressing WNK4 showed PHAII phenotypes, indicating that wild-type WNK4 protein was a positive regulator of NCC. KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein. Thus, we found that WNK4 was a target for KLHL3-mediated ubiquitination, and impaired ubiquitination of WNK4 was the common mechanism of human hereditary hypertension.
As a result of screening chemical compounds that disrupted WNK/SPAK binding, we discovered three novel compounds that could be promising seeds of new types of antihypertensive drugs.