Development of order-made treatment of hypertension by measurement of urinary transporters

2015 Fiscal Year Final Research Report

• 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
• Keywords: WNKキナーゼ

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.

Free Research Field

腎臓内科