Abstract
Familial hyperkalemic hypertension (FHHt) can be mainly attributed to increased activity of the renal Na+:Cl- cotransporter (NCC), which is caused by altered expression and regulation of the with-no-lysine (K) 1 (WNK1) or WNK4 kinases. The WNK1 gene gives rise to a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the expression of which occurs primarily in the distal convoluted tubule. The role played by KS-WNK1 in the modulation of the WNK/STE20-proline-alanine rich kinase (SPAK)/NCC pathway remains elusive. In the present study, we assessed the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK pathway. Microinjection of oocytes with human KS-WNK1 cRNA induces remarkable activation and phosphorylation of SPAK and NCC. The effect of KS-WNK1 was abrogated by eliminating a WNK-WNK-interacting domain and by a specific WNK inhibitor, WNK463, indicating that the activation of SPAK/NCC by KS-WNK1 is due to interaction with another WNK kinase. Under control conditions in oocytes, the activating serine 335 of the WNK4 T loop is not phosphorylated. In contrast, this serine becomes phosphorylated when the intracellular chloride concentration ([Cl-]i) is reduced or when KS-WNK1 is coexpressed with WNK4. KS-WNK1-mediated activation of WNK4 is not due to a decrease of the [Cl-]i. Coimmunoprecipitation analysis revealed that KS-WNK1 and WNK4 interact with each other and that WNK4 becomes autophosphorylated at serine 335 when it is associated with KS-WNK1. Together, these observations suggest that WNK4 becomes active in the presence of KS-WNK1, despite a constant [Cl-]i.
Highlights
Familiar hyperkalemic hypertension (FHHt) (OMIM 145260) is a monogenic disease caused by mutations in the with-no-lysine (K) 1 (WNK1) or WNK4 kinases or in the ubiquitin ligase complex proteins KLHL3 or Cul3 [14]
Salt-sensitive arterial hypertension with volume expansion, which reduces the activity of the renin-angiotensin system, would be expected to reduce WNK4 activity attributable to the absence of angiotensin II [5, 8]; there is a significant inverse relationship between serum potassium concentration and NaCl cotransporter (NCC) activity [29, 30], and it has been shown that serum potassium acts as a powerful modulator of NCC activity via the WNK4-STE20-proline-alanine rich kinase (SPAK)
We previously demonstrated that the injection of human L-WNK1-⌬11 cRNA into Xenopus laevis oocytes induces significant increases in NCC activity and phosphorylation [7]
Summary
Familiar hyperkalemic hypertension (FHHt) (OMIM 145260) is a monogenic disease caused by mutations in the with-no-lysine (K) 1 (WNK1) or WNK4 kinases or in the ubiquitin ligase complex proteins KLHL3 or Cul3 [14]. Studies have shown that WNK kinases, WNK4, are very sensitive to serum potassium and decreased activity of the renin angiotensin system [4, 5, 8, 30]. Salt-sensitive arterial hypertension with volume expansion, which reduces the activity of the renin-angiotensin system, would be expected to reduce WNK4 activity attributable to the absence of angiotensin II [5, 8]; there is a significant inverse relationship between serum potassium concentration and NCC activity [29, 30], and it has been shown that serum potassium acts as a powerful modulator of NCC activity via the WNK4-SPAK
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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
