SPAK and WNK kinases: a new target for blood pressure treatment?

Abstract

PURPOSE OF REVIEW:

The regulation of sodium reabsorption by the distal kidney is fundamental to blood pressure control. The clinical success of thiazide diuretics as antihypertensive drugs underscores the importance of its target, the thiazide-sensitive sodium/chloride cotransporter (NCC), in this process. However, thiazides are often ineffective as monotherapy and have significant side-effects. An understanding of NCC regulation at a molecular level may allow the design of better tolerated and more effective antihypertensive agents. The aim of this review is to provide an overview of the recent developments in the regulation of NCC, highlighting a potential new therapeutic target for the treatment of hypertension.

RECENT FINDINGS:

It has been appreciated for several years that WNK kinases affect NCC expression, following the discovery that mutations in WNK genes cause Gordon syndrome (pseudohypoaldosteronism type II), although the precise molecular mechanisms were unclear. What has emerged from further in-vitro work is a WNK signalling cascade with the STE20 kinases SPAK and OSR1 as the 'missing' intermediate kinases that are activated by WNKs. Confirmation that this WNK-SPAK cascade operates in vivo comes from work on the phenotype of a kinase-dead SPAK knockin mouse. This mouse is markedly hypotensive, salt wasting, and almost all of its NCC protein in the distal kidney is dephosphorylated. Finally, a genome-wide association study has identified an intronic SPAK polymorphism that associates with human blood pressure.

SUMMARY:

SPAK is a recently identified regulator of NCC and, hence, sodium reabsorption in the distal nephron. SPAK gene variants may also be important players in essential hypertension. If the phenotype of the kinase-dead SPAK mouse mimics pharmacological inhibition of this kinase, then SPAK is a potentially very interesting new antihypertensive drug target.

• Authors: Mark Glover, Kevin M O'shaughnessy
• Journal: Current opinion in nephrology and hypertension (Curr Opin Nephrol Hypertens) Vol. 20 Issue 1 Pg. 16-22 (Jan 2011) ISSN: 1473-6543 [Electronic] England
• PMID: 21088576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Sodium Chloride Symporters
• OXSR1 protein, human
• Protein Serine-Threonine Kinases
• STK39 protein, human
• WNK3 protein, human
• WNK4 protein, human

Topics

• Animals
• Arthrogryposis (etiology)
• Blood Pressure
• Cleft Palate (etiology)
• Clubfoot (etiology)
• Hand Deformities, Congenital (etiology)
• Humans
• Hypertension (drug therapy, genetics)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, physiology)
• Sodium Chloride Symporters (genetics, physiology)