Activation of the renal Na+:Cl− cotransporter by angiotensin II is a WNK4-dependent process

摘要: Pseudohypoaldosteronism type II is a salt-sensitive form of hypertension with hyperkalemia in humans caused by mutations the with-no-lysine kinase 4 (WNK4). Several studies have shown that WNK4 modulates activity renal Na+Cl− cotransporter, NCC. Because consequences carrying pseudoaldosteronism resemble response to intravascular volume depletion (promotion salt reabsorption without K+ secretion), condition associated high angiotensin (AngII) levels, it has been proposed AngII signaling might affect modulation In Xenopus laevis oocytes, required for NCC AngII. To demonstrate AngII-mediated regulation vivo, we used total WNK4-knockout mouse strain (WNK4−/−). mRNA and protein expression were absent WNK4−/− mice, which exhibited mild Gitelman-like syndrome, normal blood pressure, increased plasma renin activity, reduced phosphorylation at T-58. Immunohistochemistry revealed morphology distal convoluted tubule expression. Low-salt diet or infusion d induced STE20/SPS1-related proline/alanine-rich (SPAK) S-383 T-58, respectively, WNK4+/+ but not mice. Thus, absence vivo precludes SPAK promoted low-salt infusion, suggesting action on occurs via WNK4-SPAK–dependent pathway. Additionally, stimulation aldosterone secretion AngII, high-K+ diet, was impaired