WNK1 activates SGK1 to regulate the epithelial sodium channel

Xu, Bing; Stippec, Steve; Chu, Po‐Yin; Lazrak, Ahmed; Li, Xin Ji; Lee, Byung‐Hoon; English, Jessie M.; Ortega, Bernardo; Huang, Chou Long; Cobb, Melanie H.

doi:10.1073/pnas.0504422102

Cited by 191 publications

(188 citation statements)

References 61 publications

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“…Other mechanism(s) may also be involved. Consistent with this observation, WNK1 activates SGK1 leading to activation of the epithelial Na + channel ENaC (Xu et al, 2005a), a channel also responsible for Na + reabsorption in kidneys. Thus, hypertension in PHA II patients with WNK1 mutations may be caused by increased activity of both ENaC and NCC.…”

Section: Pathogenesis Of Hypertension In Pha IIsupporting

confidence: 61%

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WNKs: protein kinases with a unique kinase domain

Huang

Kuy²,

Wang³

et al. 2007

Exp Mol Med

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WNKs (with-no-lysine [K]) are a family of serine-threonine protein kinases with an atypical placement of the catalytic lysine relative to all other protein kinases. The roles of WNK kinases in regulating ion transport were first revealed by the findings that mutations of two members cause a genetic hypertension and hyperkalemia syndrome. More recent studies suggest that WNKs are pleiotropic protein kinases with important roles in many cell processes in addition to ion transport. Here, we review roles of WNK kinases in the regulation of ion balance, cell signaling, survival, and proliferation, and embryonic organ development.

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Section: Pathogenesis Of Hypertension In Pha IIsupporting

confidence: 61%

“…WNK1 activates ENaC by preventing its endocytosis associated with a Nedd4-mediated ubiquitination (Xu et al, 2005a). WNK1 and WNK4 inhibit ROMK by stimulating endocytosis of the channel via clathrin-coated vesicles (CCV) (Kahle et al, 2003;Lazrak et al, 2006;Wade et al, 2006).…”

Section: Mechanisms Of Regulation By Wnksmentioning

confidence: 99%

WNKs: protein kinases with a unique kinase domain

Huang

Kuy²,

Wang³

et al. 2007

Exp Mol Med

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“…WNK1 and WNK4 can upregulate ENaC activity through SGK1 and Nedd4 -2. 8,9 Although the BP phenotype of Period Ϫ/Ϫ mice has not been reported, these mice fed the standard diet also had higher Na ϩ excretion and lower ␣ENaC expression than WT controls. 20 Another feature not limited to Af17 Ϫ/Ϫ mice is that the changes in Na ϩ reabsorption are not accompanied by an inverse effect on K ϩ , indicating that the impaired ENaC function can not account for the complete panoply of the renal dysfunction.…”

Section: High Dietary Potassium Attenuated the Effect Of Af17mentioning

confidence: 99%

“…WNK1 and WNK4 have been shown to regulate ENaC. 8,9 A number of inherited disorders characterized by salt wasting and hypotension are caused by loss-of-function mutations impairing salt homeostasis. Examples include Bartter's and Gitelman's syndromes, with defects in six genes encoding renal tubular transporters and ion channels (reviewed in ref.…”

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confidence: 99%

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

Chen¹,

H²,

Pochynyuk

et al. 2011

Journal of the American Society of Nephrology

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The putative transcription factor AF17 upregulates the transcription of the epithelial sodium channel (ENaC) genes, but whether AF17 modulates sodium homeostasis and BP is unknown. Here, we generated Af17-deficient mice to determine whether deletion of Af17 leads to sodium wasting and low BP. Compared with wild-type mice, Af17-deficient mice had lower BP (11 mmHg), higher urine volume, and increased sodium excretion despite mildly increased plasma concentrations of aldosterone. Deletion of Af17 led to increased dimethylation of histone H3 K79 and reduced ENaC function. The attenuated function of ENaC resulted from decreased ENaC mRNA and protein expression, fewer active channels, lower open probability, and reduced effective activity. In contrast, inducing high levels of plasma aldosterone by a variety of methods completely compensated for Af17 deficiency with respect to sodium handling and BP. Taken together, these data identify Af17 as a potential locus for the maintenance of sodium and BP homeostasis and suggest that a particular histone modification is directly linked to these processes. Af17-mediated regulation of BP is largely, but not exclusively, the result of modulating ENaC, suggesting it has potential as a therapeutic target for the control of BP.

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“…Moreover, patients with WNK1 mutations do not have hypercalciuria, whereas patients with WNK4 mutations have hypercalciuria that is Ϸ6-fold more sensitive to thiazide treatment than normal individuals (13,14). A recent study by Xu et al (15) shows that WNK1 activates SGK leading to activation of ENaC. Thus, hypertension in PHA II patents with WNK1 mutations may be caused by increased activity of Na-Cl cotransporter and ENaC.…”

mentioning

confidence: 99%

Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms

Lazrak

Liu

Huang³

2006

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

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WNK kinases are serine-threonine kinases with an atypical placement of the catalytic lysine. Intronic deletions with increased expression of a ubiquitous long WNK1 transcript cause pseudohypoaldosteronism type 2 (PHA II), characterized by hypertension and hyperkalemia. Here, we report that long WNK1 inhibited ROMK1 by stimulating its endocytosis. Inhibition of ROMK by long WNK1 was synergistic with, but not dependent on, WNK4. A smaller transcript of WNK1 lacking the N-terminal 1-437 amino acids is expressed highly in the kidney. Whether expression of the KS-WNK1 (kidney-specific, KS) is altered in PHA II is not known. We found that KS-WNK1 did not inhibit ROMK1 but reversed the inhibition of ROMK1 caused by long WNK1. Consistent with the lack of inhibition by KS-WNK1, we found that amino acids 1-491 of the long WNK1 were sufficient for inhibiting ROMK. Dietary K ؉ restriction decreases ROMK abundance in the renal cortical-collecting ducts by stimulating endocytosis, an adaptative response important for conservation of K ؉ during K ؉ deficiency. We found that K ؉ restriction in rats increased whole-kidney transcript of long WNK1 while decreasing that of KS-WNK1. Thus, KS-WNK1 is a physiological antagonist of long WNK1. Hyperkalemia in PHA II patients with PHA II mutations may be caused, at least partially, by increased expression of long WNK1 with or without decreased expression of KS-WNK1. There are four mammalian WNK family members (1). WNK1, the first member identified, is Ͼ2,100 amino acids long (2). It contains an Ϸ270-aa kinase domain located near the amino terminus (e.g., amino acids 218-491 of the rat WNK1). WNK2, 3, and 4 are products of different genes and Ϸ1,200 to 1,600 amino acids in length (1, 2). The kinase domain of the four WNKs that share 85-90% sequence identity are unique in having the catalytic lysine located in the subdomain I instead of the conserved subdomain II of most protein kinases (1-3). Other conserved domains of WNK kinases include an autoinhibitory domain, 1-2 coiled-coil domains, and multiple PXXP prolinerich motifs for potential protein-protein interaction (1-4). Beyond the aforementioned conserved domains͞motifs, sequence identity among the four WNKs is much lower and few homologous regions exist.Pseudohypoaldosteronism type II (PHA II) is an autosomaldominant disease characterized by hypertension and hyperkalemia (5). Recently, Wilson et al. (6) reported that mutations of WNK1 and WNK4 cause PHA II. Mutations in the WNK1 gene are large deletions of the first intron leading to increased expression. Mutations in the WNK4 gene are missense mutations in the coding sequence outside the protein kinase domain. Several recent studies have examined the mechanisms for hypertension and hyperkalemia in PHA II patients. WNK4 inhibits the activity of the sodium chloride cotransporter. WNK4 mutants that cause disease fail to inhibit the sodium chloride cotransporter, suggesting that an increase in sodium chloride cotransporter activity in the distal convoluted tubule is a cause of hypertens...

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WNK1 activates SGK1 to regulate the epithelial sodium channel

Cited by 191 publications

References 61 publications

WNKs: protein kinases with a unique kinase domain

WNKs: protein kinases with a unique kinase domain

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms

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