Molecular physiology of the thiazide-sensitive sodium-chloride cotransporter.
OBJECTIVE
This review summarizes recent advances in the understanding of the molecular physiology and regulation of the thiazide-sensitive sodium-chloride cotransporter (NCC).


RESULTS
Mutations of with-no-lysine (WNK) kinases 1 and 4 result in hyperactivity of NCC and familial hyperkalemic hypertension, a genetic syndrome of hypertension. Recent studies have shown that WNK1 and WNK4 activate the STE20 family protein kinases Ste20-related proline/alanine-rich kinase and odd-skipped-related 1, resulting in phosphorylation and activation of NCC. Additionally, a mouse knock-in model for a WNK4 familial hyperkalemic hypertension mutant demonstrated increased Ste20-related proline/alanine-rich kinase/odd-skipped-related 1 and NCC phosphorylation. It is unclear how these studies fit with the data indicating that WNK4 inhibits NCC, and the familial hyperkalemic hypertension mutations of WNK4 are loss-of-function mutations. Another WNK kinase, WNK3, also regulates NCC, activating NCC and antagonizing the effect of WNK4. Extracellular signal-related kinase 1/2 mitogen-activated protein kinase activation by Ras guanyl nucleotide-releasing protein 1 is another kinase pathway that appears to be a potent regulator of NCC. Other studies have described a role for angiotensin II in pressure natriuresis via actions on NCC. Recent studies examining the hormonal regulation of NCC have implicated angiotensin II and aldosterone in regulation of the WNK4-Ste20-related proline/alanine-rich kinase-NCC pathway.


CONCLUSIONS
NCC is subject to a complex regulatory network of kinases, which appear quite sensitive to alterations of the hormonal and physiologic milieu.
Ko
Benjamin
B
Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Hoover
Robert S
RS
D000818:Animals; D004232:Diuretics / Q000494:pharmacology*; D006728:Hormones / Q000502:physiology; D006801:Humans; D051379:Mice; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D049992:Sodium Chloride Symporters / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D049971:Thiazides / Q000494:pharmacology*
D004232:Diuretics; D006728:Hormones; D049992:Sodium Chloride Symporters; D049971:Thiazides; D011494:Protein Kinases