| Project/Area Number |
26670428
|
|---|
| Research Category |
Grant-in-Aid for Challenging Exploratory Research
|
| Allocation Type | Multi-year Fund |
|---|
| Research Field |
Kidney internal medicine
|
|---|
| Research Institution | Tokyo Medical and Dental University |
|---|
Principal Investigator |
SOHARA EISEI 東京医科歯科大学, 医歯(薬)学総合研究科, 准教授 (90510355)
|
|---|
| Project Period (FY) |
2014-04-01 – 2016-03-31
|
| Project Status |
Completed (Fiscal Year 2015)
|
| Budget Amount *help |
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
|
|---|
| Keywords | WNKキナーゼ / 塩分感受性 / AQP2 / リン / 塩分感受性高血圧 / KLHL3 |
|---|
| Outline of Final Research Achievements |
Pseudohypoaldosteronism type II (PHAII) is a hereditary disease characterized by salt-sensitive hypertension, hyperkalemia and metabolic acidosis, and genes encoding with-no-lysine kinase 1 (WNK1) and WNK4 kinases are known to be responsible. Recently, Kelch-like 3 (KLHL3) and Cullin3, components of KLHL3-Cullin3 E3 ligase, were newly identified as responsible for PHAII. To investigate the pathogenesis of PHAII caused by KLHL3 mutation, we generated KLHL3R528H/+ knock-in mice. KLHL3R528H/+ knock-in mouse is an ideal mouse model of PHAII. Interestingly, the protein expression of both WNK1 and WNK4 was significantly increased in the KLHL3R528H/+ mouse kidney, confirming that increases in these WNK kinases activated the WNK-OSR1/SPAK-NCC phosphorylation cascade in KLHL3R528H/+ knock-in mice. Thus, we found that increased protein expression levels of WNK1 and WNK4 kinases cause PHAII by KLHL3 R528H mutation due to impaired KLHL3-Cullin3-mediated ubiquitination.
|
