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Argaiz ER, Chavez-Canales M, Ostrosky-Frid M, Rodríguez-Gama A, Vázquez N, Gonzalez-Rodriguez X, Garcia-Valdes J, Hadchouel J, Ellison D, Gamba G.
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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.
Bazúa-Valenti,
The Effect of WNK4 on the Na+-Cl- Cotransporter Is Modulated by Intracellular Chloride.
2015, Pubmed,
Xenbase
Bazúa-Valenti,
The Effect of WNK4 on the Na+-Cl- Cotransporter Is Modulated by Intracellular Chloride.
2015,
Pubmed
,
Xenbase Bazúa-Valenti,
Revisiting the NaCl cotransporter regulation by with-no-lysine kinases.
2015,
Pubmed Boyd-Shiwarski,
Potassium-regulated distal tubule WNK bodies are kidney-specific WNK1 dependent.
2018,
Pubmed Castañeda-Bueno,
Modulation of NCC activity by low and high K(+) intake: insights into the signaling pathways involved.
2014,
Pubmed Castañeda-Bueno,
Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process.
2012,
Pubmed
,
Xenbase Chang,
Slc26a9--anion exchanger, channel and Na+ transporter.
2009,
Pubmed
,
Xenbase Chávez-Canales,
WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4.
2014,
Pubmed
,
Xenbase Chiga,
Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone.
2008,
Pubmed Delaloy,
Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform.
2003,
Pubmed Ellison,
Potassium and Its Discontents: New Insight, New Treatments.
2016,
Pubmed Gamba,
Regulation of the renal Na+-Cl- cotransporter by phosphorylation and ubiquitylation.
2012,
Pubmed Gamba,
Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney.
1994,
Pubmed
,
Xenbase Grimm,
Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules.
2017,
Pubmed Hadchouel,
Regulation of Renal Electrolyte Transport by WNK and SPAK-OSR1 Kinases.
2016,
Pubmed Hadchouel,
Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney-specific isoform of WNK1 and prevents hypertension.
2010,
Pubmed Jiang,
WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4.
2007,
Pubmed
,
Xenbase Lalioti,
Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule.
2006,
Pubmed Lifton,
Molecular mechanisms of human hypertension.
2001,
Pubmed Liu,
Downregulation of NCC and NKCC2 cotransporters by kidney-specific WNK1 revealed by gene disruption and transgenic mouse models.
2011,
Pubmed
,
Xenbase Nessler,
Evidence for activation of endogenous transporters in Xenopus laevis oocytes expressing the Plasmodium falciparum chloroquine resistance transporter, PfCRT.
2004,
Pubmed
,
Xenbase Ohta,
The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction.
2013,
Pubmed O'Reilly,
WNK1, a gene within a novel blood pressure control pathway, tissue-specifically generates radically different isoforms with and without a kinase domain.
2003,
Pubmed Pacheco-Alvarez,
The Na+:Cl- cotransporter is activated and phosphorylated at the amino-terminal domain upon intracellular chloride depletion.
2006,
Pubmed
,
Xenbase Piala,
Chloride sensing by WNK1 involves inhibition of autophosphorylation.
2014,
Pubmed Richardson,
Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1.
2008,
Pubmed San-Cristobal,
WNK3 and WNK4 amino-terminal domain defines their effect on the renal Na+-Cl- cotransporter.
2008,
Pubmed
,
Xenbase Shibata,
Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4.
2013,
Pubmed Subramanya,
Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform.
2006,
Pubmed
,
Xenbase Terker,
Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis.
2016,
Pubmed Terker,
Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride.
2015,
Pubmed Thastrup,
SPAK/OSR1 regulate NKCC1 and WNK activity: analysis of WNK isoform interactions and activation by T-loop trans-autophosphorylation.
2012,
Pubmed Vidal-Petiot,
A new methodology for quantification of alternatively spliced exons reveals a highly tissue-specific expression pattern of WNK1 isoforms.
2012,
Pubmed Vidal-Petiot,
WNK1-related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron.
2013,
Pubmed Vitari,
Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1.
2006,
Pubmed Vitari,
The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases.
2005,
Pubmed Wakabayashi,
Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension.
2013,
Pubmed Wilson,
Human hypertension caused by mutations in WNK kinases.
2001,
Pubmed Wilson,
Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.
2003,
Pubmed
,
Xenbase Wu,
Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.
2013,
Pubmed
,
Xenbase Yamada,
Small-molecule WNK inhibition regulates cardiovascular and renal function.
2016,
Pubmed Yang,
Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model.
2007,
Pubmed
