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2016 Fiscal Year Final Research Report

Mechanisms of regulation of ion transporters by ER stress

Research Project

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Project/Area Number 15K19446
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Kidney internal medicine
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Inoue Yuichi  東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (50735834)

Project Period (FY) 2015-04-01 – 2017-03-31
Keywords電解質 / WNKシグナル
Outline of Final Research Achievements

Mutations in the with-no-lysine kinase 1 (WNK1), WNK4, kelch-like 3 (KLHL3), and cullin3 (CUL3) genes are known to cause the hereditary disease pseudohypoaldosteronism type II (PHAII).However, physiological in vivo roles of KLHL3 remain unclear. Therefore, here we generated KLHL3-/- mice that expressed β-galactosidase (β-Gal) under the control of the endogenous KLHL3 promoter. Immunoblots of β-Gal and LacZ staining revealed that KLHL3 was expressed in some organs, such as brain. However, the expression levels of WNK kinases were not increased in any of these organs other than the kidney. KLHL3-/- mice also showed PHAII-like phenotypes, whereas KLHL3+/- mice did not. This clearly demonstrates that the heterozygous deletion of KLHL3 was not sufficient to cause PHAII, indicating that autosomal dominant type PHAII is caused by the dominant negative effect of mutant KLHL3. We further demonstrated that the dimerization of KLHL3 can explain this dominant negative effect.

Free Research Field

腎臓内科

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Published: 2018-03-22  

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