WNK1-related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron.
Large deletions in the first intron of the With No lysine (K) 1 (WNK1) gene are responsible for Familial Hyperkalemic Hypertension (FHHt), a rare form of human hypertension associated with hyperkalemia and hyperchloremic metabolic acidosis. We generated a mouse model of WNK1-associated FHHt to explore the consequences of this intronic deletion. WNK1(+/FHHt) mice display all clinical and biological signs of FHHt. This phenotype results from increased expression of long WNK1 (L-WNK1), the ubiquitous kinase isoform of WNK1, in the distal convoluted tubule, which in turn, stimulates the activity of the Na-Cl cotransporter. We also show that the activity of the epithelial sodium channel is not altered in FHHt mice, suggesting that other mechanisms are responsible for the hyperkalemia and acidosis in this model. Finally, we observe a decreased expression of the renal outer medullary potassium channel in the late distal convoluted tubule of WNK1(+/FHHt) mice, which could contribute to the hyperkalemia. In summary, our study provides insights into the in vivo mechanisms underlying the pathogenesis of WNK1-mediated FHHt and further corroborates the importance of WNK1 in ion homeostasis and blood pressure.
Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, F-75015 Paris, France.
Emmanuelle
E
Vidal-Petiot
Emilie
E
Elvira-Matelot
Kerim
K
Mutig
Christelle
C
Soukaseum
Véronique
V
Baudrie
Shengnan
S
Wu
Lydie
L
Cheval
Elizabeth
E
Huc
Michèle
M
Cambillau
Sebastian
S
Bachmann
Alain
A
Doucet
Xavier
X
Jeunemaitre
Juliette
J
Hadchouel
D000818:Animals; D053503:Epithelial Sodium Channels / Q000378:metabolism; D017353:Gene Deletion; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011546:Pseudohypoaldosteronism / Q000235:genetics* / Q000378:metabolism; D000076204:WNK Lysine-Deficient Protein Kinase 1
D053503:Epithelial Sodium Channels; C510693:Kcnj1 protein, mouse; D015778:Minor Histocompatibility Antigens; D024661:Potassium Channels, Inwardly Rectifying; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498744:Wnk1 protein, mouse
potassium balance; sodium transport; transgenic mouse