Role of WNK kinases in regulating tubular salt and potassium transport and in the development of hypertension.
A recently discovered family of protein kinases is responsible for an autosomal-dominant disease known as Gordon's syndrome or pseudohypoaldosteronism type II (PHA-II) that features hyperkalemia and hyperchloremic metabolic acidosis, accompanied by hypertension and hypercalciuria. Four genes have been described in this kinase family, which has been named WNK, due to the absence of a key lysine in kinase subdomain II (with no K kinases). Two of these genes, WNK1 and WNK4 located in human chromosomes 12 and 17, respectively, are responsible for PHA-II. Immunohystochemical analysis revealed that WNK1 and WNK4 are predominantly expressed in the distal convoluted tubule and collecting duct. The physiological studies have shown that WNK4 downregulates the activity of ion transport pathways expressed in these nephron segments, such as the apical thiazide-sensitive Na+-Cl- cotransporter and apical secretory K+ channel ROMK, as well as upregulates paracellular chloride transport and phosphorylation of tight junction proteins such as claudins. In addition, WNK4 downregulates other Cl- influx pathways such as the basolateral Na+-K+-2Cl- cotransporter and Cl-/HCO3- exchanger. WNK4 mutations behave as a loss of function for the Na+-Cl- cotransporter and a gain of function when it comes to ROMK and claudins. These dual effects of WNK4 mutations fit with proposed mechanisms for developing electrolyte abnormalities and hypertension in PHA-II and point to WNK4 as a multifunctional regulator of diverse ion transporters.
Gamba
Gerardo
G
Molecular Physiology Unit, Instituto de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Tlalpan 14000, México City, Mexico. gamba@biomedicas.unam.mx
D015536:Down-Regulation; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins; D017136:Ion Transport / Q000502:physiology; D007684:Kidney Tubules / Q000502:physiology*; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D011188:Potassium / Q000493:pharmacokinetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000494:pharmacology*; D012965:Sodium Chloride / Q000493:pharmacokinetics*; D000076204:WNK Lysine-Deficient Protein Kinase 1
D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D012965:Sodium Chloride; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C433806:WNK4 protein, human; D011188:Potassium