WNK-SPAK-NCC Cascade Revisited
WNK1 Stimulates the Activity of the Na-Cl Cotransporter via SPAK, an Effect Antagonized by WNK4
The with-no-lysine (K) kinases, WNK1 and WNK4, are key regulators of blood pressure. Their mutations lead to familial hyperkalemic hypertension (FHHt), associated with an activation of the Na-Cl cotransporter (NCC). Although it is clear that WNK4 mutants activate NCC via Ste20 proline-alanine–rich kinase, the mechanisms responsible for WNK1-related FHHt and alterations in NCC activity are not as clear. We tested whether WNK1 modulates NCC through WNK4, as predicted by some models, by crossing our recently developed WNK1-FHHt mice (WNK1+/FHHt) with WNK4−/− mice. Surprisingly, the activated NCC, hypertension, and hyperkalemia of WNK1+/FHHt mice remain in the absence of WNK4. We demonstrate that WNK1 powerfully stimulates NCC in a WNK4-independent and Ste20 proline-alanine–rich kinase–dependent manner. Moreover, WNK4 decreases the WNK1 and WNK3-mediated activation of NCC. Finally, the formation of oligomers of WNK kinases through their C-terminal coiled-coil domain is essential for their activity toward NCC. In conclusion, WNK kinases form a network in which WNK4 associates with WNK1 and WNK3 to regulate NCC.
- familial hypertensive hyperkalemia
- hypertension, renal
- kidney tubules, distal
- mice, knockout
- pseudohypoaldosteronism, type II
- water-electrolyte balance
- Xenopus laevis
- Received June 17, 2014.
- Revision received July 3, 2014.
- Accepted July 16, 2014.
- © 2014 American Heart Association, Inc.