Molecular physiology of the thiazide-sensitive sodium-chloride cotransporter

Abstract

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

Recent findings: 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.

Summary: NCC is subject to a complex regulatory network of kinases, which appear quite sensitive to alterations of the hormonal and physiologic milieu.

Figure 1

Contrasting theories into the mechanism of FHHt mutations. A. Mutant WNK4 as a Loss of Function. WNK4 acts to inhibit NCC activity. Mutant WNK4 is unable to inhibit NCC, resulting in a net increase in NCC activity. B. Mutant WNK4 as a Gain of Function. In the normal state, WNK4 activates OSR1/SPAK, which in turn activates NCC, resulting in enhanced NCC activity. The mutant WNK4 is a gain of function mutation, resulting in increased OSR1/SPAK activation and therefore increased NCC activity. C. Mutant WNK1 acting via WNK4. WNK1 normally acts to inhibit WNK4. Since WNK4 inhibits NCC, this has the net result of increasing NCC activity. Mutant WNK1 is a gain of function, enhancing its ability to inhibit WNK4 and therefore increasing NCC activity. D. Mutant WNK1 Acting Via OSR1/SPAK. WNK1 normally acts to increase OSR1/SPAK phosphorylation, which increases NCC activity. Mutant WNK1 is a gain of function mutation, resulting in increased OSR1/SPAK activity, which in turn increases NCC activity.

Figure 2

Proposed Schematic of Molecular Pathways of NCC Regulation. Binding of ligand to G-protein coupled (αq) receptor stimulates phospholipase C (PLCβ). PLCβ activation triggers diacylglerol (DAG) release, in turn stimulating RasGRP1, Ras, Raf, MEK1/2, and ERK1/2. ERK1/2 causes enhanced ubiquitination of NCC, ultimately reducing NCC activity. WNK4 appears to directly inhibit NCC activity. WNK1 and WNK3 appear to inhibit WNK4. WNK3 may directly activate NCC as well. WNK1 and WNK4 stimulate OSR1/SPAK. OSR1/SPAK activates NCC. Stimulation of the mineralcorticoid receptor (MR) and/or angiotensin II receptor (AIIR) may act through WNK4 to activate OSR1/SPAK (* = Under certain hormonal/physiologic stimuli, WNK4 acts to stimulate OSR1/SPAK), stimulating NCC.