KLHL2/3 as molecular targets to modulate WNK kinases

2016 Fiscal Year Final Research Report

• Project/Area Number: 15K15327
• 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: UCHIDA SHINICIH 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (50262184)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: 高血圧 / 水・電荷室 / キナーゼ / E3リガーゼ

Outline of Final Research Achievements

We evaluated the effects of overexpression of KLHL2 and KLHL3 on WNK protein abundance in cultured cells. Overexpression of KLHL2 or KLHL3 along with WNK kinases dramatically decreased WNK protein abundance. Thus, it would be possible to modulate WNK signaling in vivo by overexpressing KLHL2 or KLHL3. Further study using KLHL2/3 transgenic mice would be necessary. We also evaluated the in vivo roles of KLHL2 and KLHL3 by generating and analyzing KLHL2 and KLHL3 knockout mice. We found that KLHL2 knockout induced WNK4 protein level not in cortex but in medulla. In KLHL3 knockout mice, the major changes of WNK protein observed in various organs was WNK1 and WNK4 in the kidney. Although the abundant expression of KLHL3 in brain was observed, WNK proteins in the whole brain was not increased, suggesting the compensation by KLHL2 or the increased in specific cell populations. We plan further study using the double knockout of KLHL2 and KLHL3.

Free Research Field

腎臓内科学