Document Detail

An inducible transgenic mouse model for familial hypertension with hyperkalaemia (Gordon's syndrome or pseudohypoaldosteronism type II).
MedLine Citation:
PMID:  23336180     Owner:  NLM     Status:  MEDLINE    
Mutations in the novel serine/threonine WNK [With No lysine (=K)] kinases WNK1 and WNK4 cause PHAII (pseudohypoaldosteronism type II or Gordon's syndrome), a rare monogenic syndrome which causes hypertension and hyperkalaemia on a background of a normal glomerular filtration rate. Current animal models for PHAII recapitulate some aspects of the disease phenotype, but give no clues to how rapidly the phenotype emerges or whether it is reversible. To this end we have created an inducible PHAII transgenic animal model that expresses a human disease-causing WNK4 mutation, WNK4 Q565E, under the control of the Tet-On system. Several PHAII inducible transgenic mouse lines were created, each with differing TG (transgene) copy numbers and displaying varying degrees of TG expression (low, medium and high). Each of these transgenic lines demonstrated similar elevations of BP (blood pressure) and plasma potassium after 4 weeks of TG induction. Withdrawal of doxycycline switched off mutant TG expression and the disappearance of the PHAII phenotype. Western blotting of microdissected kidney nephron segments confirmed that expression of the thiazide-sensitive NCC (Na⁺-Cl⁻ co-transporter) was increased, as expected, in the distal convoluted tubule when transgenic mice were induced with doxycycline. The kidneys of these mice also do not show the morphological changes seen in the previous transgenic model expressing the same mutant form of WNK4. This inducible model shows, for the first time, that in vivo expression of a mutant WNK4 protein is sufficient to cause the rapid and reversible appearance of a PHAII disease phenotype in mice.
Jabed A Chowdhury; Che-Hsiung Liu; Annie M Zuber; Kevin M O'Shaughnessy
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical science (London, England : 1979)     Volume:  124     ISSN:  1470-8736     ISO Abbreviation:  Clin. Sci.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-02-26     Completed Date:  2013-04-18     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  7905731     Medline TA:  Clin Sci (Lond)     Country:  England    
Other Details:
Languages:  eng     Pagination:  701-8     Citation Subset:  IM    
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MeSH Terms
Biological Markers / blood
Blood Pressure
Blotting, Western
Disease Models, Animal
Doxycycline / pharmacology
Gene Expression Regulation, Enzymologic / drug effects
In Situ Hybridization, Fluorescence
Kidney / enzymology*,  physiopathology
Mice, Inbred C57BL
Mice, Transgenic
Potassium / blood
Protein-Serine-Threonine Kinases / genetics,  metabolism*
Pseudohypoaldosteronism / blood,  enzymology*,  genetics,  physiopathology
Sodium Chloride Symporters / metabolism
Time Factors
Grant Support
PG/09/089//British Heart Foundation; PG/09/089/28063//British Heart Foundation
Reg. No./Substance:
0/Biological Markers; 0/Sodium Chloride Symporters; EC 2.7.1.-/Prkwnk4 protein, mouse; EC Kinases; N12000U13O/Doxycycline; RWP5GA015D/Potassium

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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