Discovery of genomic mutations in WNK [With-No-Lysine (K)] kinase 1 and 4 responsible for pseudohypoaldosteronism type II (PHAII) featuring an autosomal-dominant salt-sensitive hypertension with hyperkalemia and metabolic acido-sis opens the avenue of the new understanding in renal tubular sodium (Na+) regulation. In mammalian, WNK kinases (WNK1-4) are a group of serine/threonine proteins. In in vitro studies, WNK1 and 4 could enhance the phosphorylation of SPAK [STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase] and OSR1(Oxidative Stress-Response kinase 1)
known as the upstream activators of NKCC2 [Na+-K+-2Cl- cotransproter 2] and NCC [Na+-Cl- cotransproter] in the thick ascending limbs and distal convoluted tubules of kidney, respectively. Several genetically-altered mice models have been created to explore the in vivo function of WNK, SPAK/OSR1 and NCC. PHAII-mutant WNK4 transgenic/knock-in mice exhibit typical PHAII phenotype with an increased phosphorylation and function of SPAK/OSR1 and NCC. On the other hand, mice with attenuated WNK4 or SPAK expression manifest Gitelman-like syndrome, the mirror images of PHAII,
with a reduced phosphorylation and function of NCC. Mice with altered WNK1 expression also have abnormal blood pressure and disturbed renal Na
+ regulation. Polymorphisms in genes encoding WNK1, WNK4, SPAK and NCC are also associated with essential hypertension and WNK-SPAK/OSR-NCC signaling is also reported to involved in salt-sensitive hypertension. This review summarizes the important studies in the molecular athophysiology of WNK-SPAK/OSR1-N(K)CC signaling in the kidneys from cell and transgenic animal models to human studies.