Abstract
It has recently been shown that the WNK [with-no-K(Lys)] kinases (WNK1, WNK2, WNK3 and WNK4) have vital roles in the control of salt homeostasis and blood pressure. This Commentary focuses on recent findings that have uncovered the backbone of a novel signal-transduction network that is controlled by WNK kinases. Under hyperosmotic or hypotonic low-Cl- conditions, WNK isoforms are activated, and subsequently phosphorylate and activate the related protein kinases SPAK and OSR1. SPAK and OSR1 phosphorylate and activate ion co-transporters that include NCC, NKCC1 and NKCC2, which are targets for the commonly used blood-pressure-lowering thiazide-diuretic and loop-diuretic drugs. The finding that mutations in WNK1, WNK4, NCC and NKCC2 cause inherited blood-pressure syndromes in humans highlights the importance of these enzymes. We argue that these new findings indicate that SPAK and OSR1 are promising drug targets for the treatment of hypertension, because inhibiting these enzymes would reduce NCC and NKCC2 activity and thereby suppress renal salt re-absorption. We also discuss unresolved and controversial questions in this field of research.
Highlights
About one in four adults suffers from high blood pressure, a largely asymptomatic condition that is a major risk factor for stroke, congestive heart failure and kidney disease (O’Shaughnessy and Karet, 2006)
Sequence alignments indicate that SPS1related proline/alanine-rich kinase (SPAK) and oxidative stressresponsive kinase 1 (OSR1) phosphorylation sites on NKCC1 are conserved in human and mouse Na+/Cl– co-transporter (NCC) and NKCC2 (Fig. 3B), which suggests that the WNKSPAK/OSR1 pathway activates these co-transporters
The discovery that WNK kinases are upstream activators of SPAK and OSR1, coupled with recent studies that demonstrate that the activity of renal ion co-transporters such as NCC is controlled by SPAK or OSR1, has demonstrated that the WNK-SPAK/OSR1 signalling pathway is an important component of blood-pressure regulation
Summary
About one in four adults suffers from high blood pressure (hypertension), a largely asymptomatic condition that is a major risk factor for stroke, congestive heart failure and kidney disease (O’Shaughnessy and Karet, 2006). Loss-of-function mutations of the kidney-specific NCC and NKCC2 co-transporters result in the low-blood-pressure conditions Gitelman’s syndrome and Bartter’s type I syndrome, respectively (Simon et al, 1996a; Simon et al, 1996b) It has been appreciated for some time that the activity of SLC12 ion co-transporters is controlled by phosphorylation and the external osmotic environment (Haas et al, 1995; Lytle and Forbush, 1996; Torchia et al, 1992), but little was previously understood about the signalling networks that regulated these enzymes. SLC12A1 (NKCC2) SLC12A2 (NKCC1) SLC12A3 (NCC) SLC12A4 (KCC1) SLC12A5 (KCC2) SLC12A6 (KCC3) SLC12A7 (KCC4) SLC12A8 (CCC9) SLC12A9 (CIP)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
