title: Revisiting the NaCl cotransporter regulation by with-no-lysine kinases.
abstract: The renal thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) is the salt transporter in the distal convoluted tubule. Its activity is fundamental for defining blood pressure levels. Decreased NCC activity is associated with salt-remediable arterial hypotension with hypokalemia (Gitelman disease), while increased activity results in salt-sensitive arterial hypertension with hyperkalemia (pseudohypoaldosteronism type II; PHAII). The discovery of four different genes causing PHAII revealed a complex multiprotein system that regulates the activity of NCC. Two genes encode for with-no-lysine (K) kinases WNK1 and WNK4, while two encode for kelch-like 3 (KLHL3) and cullin 3 (CUL3) proteins that form a RING type E3 ubiquitin ligase complex. Extensive research has shown that WNK1 and WNK4 are the targets for the KLHL3-CUL3 complex and that WNKs modulate the activity of NCC by means of intermediary Ste20-type kinases known as SPAK or OSR1. The understanding of the effect of WNKs on NCC is a complex issue, but recent evidence discussed in this review suggests that we could be reaching the end of the dark ages regarding this matter.
authors: Molecular Physiology Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors: Silvana
authors: S
authors: Bazúa-Valenti
authors: Molecular Physiology Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico gamba@biomedicas.unam.mx.
authors: Gerardo
authors: G
authors: Gamba
mesh_terms: D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D028021:Sodium-Potassium-Chloride Symporters; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D008239:Lysine
keywords: WNK4; distal tubule; diuretics; hypertension; ion transport