An inducible transgenic mouse model for Familial Hypertension with Hyperkalaemia (Gordon Syndrome or Pseudohypoaldosteronism Type II).

Mutations in the novel serine/threonine WNK (With No lysine [=K]) kinases, WNK1 and WNK4, cause Pseudohypoaldosteronism type II (PHAII or Gordon Syndrome (PHAII)), a rare monogenic syndrome which causes hypertension and hyperkalemia 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 transgene (TG) copy numbers and displaying varying degrees of transgene expression (low, medium and high). Each of these transgenic lines demonstrated similar elevations of blood pressure and plasma potassium after 4 weeks of transgene induction. Withdrawal of doxycycline switched off mutant transgene expression and the disappearance of the PHAII phenotype. Western blotting of microdissected kidney nephron segments confirmed that expression of the thiazide-sensitive sodium chloride cotransporter (NCC) 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 mod...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research