The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex

Yang, Chao; Zhu, Xiaoman; Ellison, David H.

doi:10.1172/jci32033

Cited by 120 publications

(148 citation statements)

References 40 publications

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“…The activation of NCC by WNK3-18a has been corroborated by other groups (7,32). In the present study, we tested the effects of all potential WNK3 variants on the activity of these cotransporters.…”

Section: Effects Of Wnk3 Variants On the Sodium-coupled Chloride Cotrsupporting

confidence: 66%

“…WNKs are complex kinases that are still poorly understood, but it seems that minimal disruption of their primary structures can prevent or switch their mode of action toward a particular target (13,23,29,32). For instance, although the effect of WNK3-18a on NCC is clearly dependent on its kinase activity, Yang et al (32) have shown that a similar effect can be obtained by the WNK3 carboxyl terminal domain in the complete absence of the kinase domain. For this reason, all WNK variants used in this study were completely sequenced to avoid any unwanted mutations that could result in truncated or altered proteins.…”

Section: C604mentioning

confidence: 99%

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Similar effects of all WNK3 variants on SLC12 cotransporters

Cruz-Rangel

Melo

Vázquez

et al. 2011

American Journal of Physiology-Cell Physiology

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kinase 3 (WNK3) is a member of a subfamily of serine/threonine kinases that modulate the activity of the electroneutral cation-coupled chloride cotransporters. WNK3 activates NKCC1/2 and NCC and inhibits the KCCs. Four splice variants are generated from the WNK3 gene. Our previous studies focused on the WNK3-18a variant. However, it has been suggested that other variants could have different effects on the cotransporters. Thus, the present study was designed to define the effects of all WNK3 variants on members of the SLC12 family. By RT-PCR from a fetal brain library, exons 18b and 22 were separately amplified and subcloned into the original WNK3-18a or catalytically inactive WNK3-D294A to obtain all four potential combinations with and without catalytic activity (18a, 18aϩ22, 18b, and 18bϩ22). The basal activity of the cotransporters and the effects of WNK3 isoforms were assessed in Xenopus laevis oocytes coinjected with each of the WNK3 variant cRNAs. In isotonic conditions, the basal activity of NCC and NKCC1/2 were increased by coinjection with any of the WNK3. The positive effects occurred even in hypotonic conditions, in which the basal activity of NKCC1 is completely prevented. Consistent with these observations, when expressed in hypotonicity, all KCCs were active, but in the presence of any of the WNK3 variants, KCC activity was completely reduced. That is, NKCC1/2 and NCC were inhibited, even in hypertonicity, while KCCs were activated, even in isotonic conditions. We conclude that the effects of all WNK3 variants toward SLC12 proteins are similar.

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Section: Effects Of Wnk3 Variants On the Sodium-coupled Chloride Cotrsupporting

confidence: 66%

Section: C604mentioning

confidence: 99%

Similar effects of all WNK3 variants on SLC12 cotransporters

Cruz-Rangel

Melo

Vázquez

et al. 2011

American Journal of Physiology-Cell Physiology

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“…Similar to WNK4 regulation on NCC (29,32,33), WT-WNK4 inhibits TRPC3 activity by regulating its surface abundance, which was dependent on the kinase activity of WNK4. Similarly, parallel to the effect on NCC, the aberrant regulation by WNK4 Q562E increased the surface expression of TRPC3 and thus raised [Ca 2+ ] i .…”

Section: Discussionmentioning

confidence: 97%

“…Hence, regulatory pathways of renal ion transport that have been revealed by the discovery of WNK4 mutations in PHAII patients provide valuable insights into the pathogenesis of hypertension. To date, fluid retention due to the increased Na + and fluid reabsorption by the kidney through increased activity of NCC is considered as the sole mechanism for the increased blood pressure in PHAII patients harboring the WNK4 Q562E mutation (5,(27)(28)(29). However, the expression of WNK4 in diverse extrarenal tissues (11) suggests that an additional pathway may contribute to the elevated blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature

Park¹,

Kim²,

Choi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the serine-threonine kinase with-no-lysine 4 (WNK4) cause pseudohypoaldosteronism type 2 (PHAII), a Mendelian form of human hypertension. WNK4 regulates diverse ion transporters in the kidney, and dysregulation of renal transporters is considered the main cause of the WNK4 mutation-associated hypertension. Another determinant of hypertension is vascular tone that is regulated by Ca 2+ -dependent blood vessel constriction. However, the role of WNK4 in vasoconstriction as part of its function to regulate blood pressure is not known. Here, we report that WNK4 is a unique modulator of blood pressure by restricting Ca 2+ influx via the transient receptor potential canonical 3 (TRPC3) channel in the vasculature. Loss of WNK4 markedly augmented TRPC3-mediated Ca 2+ influx in vascular smooth muscle cells (VSMCs) in response to α-adrenoreceptor stimulation, which is the pathological hallmark of hypertension in resistance arteries. Notably, WNK4 depletion induced hypertrophic cell growth in VSMCs and increased vasoconstriction in small mesenteric arteries via TRPC3-mediated Ca 2+ influx. In addition, WNK4 mutants harboring the Q562E PHAII-causing or the D318A kinase-inactive mutation failed to mediate TRPC3 inhibition. These results define a previously undescribed function of WNK4 and reveal a unique therapeutic target to control blood pressure in WNK4-related hypertension.H ypertension, or elevated arterial blood pressure, is one of the most common diseases in industrialized countries, increasing the risk of a wide spectrum of cardiovascular illnesses including stroke, congestive heart failure, and myocardial infarction (1). More than 90% of hypertensive patients are classified as essential hypertension because of the lack of knowledge regarding the gene identity involved in blood pressure regulation (2, 3). In the last few years, most attention has been focused on the with-no-lysine (WNK) kinases, including WNK4, that were found mutated in patients with pseudohypoaldosteronism type 2 (PHAII; Online Mendelian Inheritance in Man no. 145260), which is a rare autosomal dominant disorder featuring hypertension associated with hyperkalemia, hyperchloremia, and metabolic acidosis (4).Mice harboring the PHAII-causing WNK4 mutations Q562E (5) and D561A (6) reconstituted the phenotypes observed in PHAII patients. Deletion of the Na + Cl − cotransporter (NCC) reversed most of the phenotypes seen in the transgenic mice harboring the PHAII-causing WNK4 mutants (5), which indicated that aberrant regulation of NCC by the mutant WNK4 is critically involved in the pathogenesis of PHAII. This finding led to the suggestion that increased Na + in systemic fluids by the altered NCC activity is associated with elevated blood pressure (7-10). Another important aspect of hypertension is vascular tone. However, despite the diverse extrarenal tissue distribution of WNK4 (11), the expression and function of WNK4 in the resistance artery and the role in vasoconstriction as part of its function to regulate blood pressure has not been c...

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“…Unlike WNK4, WNK3 stimulates NCC activity in Xenopus oocytes. 51,52 WNK3 and WNK4 share a high degree of amino acid identity within the kinase domain but a much lower degree of amino acid identity in the amino and carboxyl terminal domains. San-Cristobal et al 53 reported that amino terminus of WNK3 or WNK4 plays an important role in regulation of NCC activity.…”

Section: Discussionmentioning

confidence: 99%

WNK4 Enhances the Degradation of NCC through a Sortilin-Mediated Lysosomal Pathway

Zhou¹,

Zhuang

et al. 2010

Journal of the American Society of Nephrology

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WNK kinase is a serine/threonine kinase that plays an important role in electrolyte homeostasis. WNK4 significantly inhibits the surface expression of the sodium chloride co-transporter (NCC) by enhancing the degradation of NCC through a lysosomal pathway, but the mechanisms underlying this trafficking are unknown. Here, we investigated the effect of the lysosomal targeting receptor sortilin on NCC expression and degradation. In Cos-7 cells, we observed that the presence of WNK4 reduced the steady-state amount of NCC by approximately half. Co-transfection with truncated sortilin (a dominant negative mutant) prevented this WNK4-induced reduction in NCC. NCC immunoprecipitated with both wild-type sortilin and, to a lesser extent, truncated sortilin. Immunostaining revealed that WNK4 increased the co-localization of NCC with the lysosomal marker cathepsin D, and NCC co-localized with wild-type sortilin, truncated sortilin, and WNK4 in the perinuclear region. These findings suggest that WNK4 promotes NCC targeting to the lysosome for degradation via a mechanism involving sortilin.

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The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex

Cited by 120 publications

References 40 publications

Similar effects of all WNK3 variants on SLC12 cotransporters

Similar effects of all WNK3 variants on SLC12 cotransporters

Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature

WNK4 Enhances the Degradation of NCC through a Sortilin-Mediated Lysosomal Pathway

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