title: An inducible transgenic mouse model for familial hypertension with hyperkalaemia (Gordon's syndrome or pseudohypoaldosteronism type II).
abstract: 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.
authors: Clinical Pharmacology Unit, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.
authors: Jabed A
authors: JA
authors: Chowdhury
authors: Che-Hsiung
authors: CH
authors: Liu
authors: Annie M
authors: AM
authors: Zuber
authors: Kevin M
authors: KM
authors: O'Shaughnessy
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure; D015153:Blotting, Western; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007668:Kidney / Q000201:enzymology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D011188:Potassium / Q000097:blood; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011546:Pseudohypoaldosteronism / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D049992:Sodium Chloride Symporters / Q000378:metabolism; D013997:Time Factors
chemical_list: D015415:Biomarkers; D049992:Sodium Chloride Symporters; C499024:Prkwnk4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004318:Doxycycline; D011188:Potassium