Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate.

Gordon, Richard D.

doi:10.1161/01.hyp.8.2.93

Cited by 205 publications

(131 citation statements)

References 46 publications

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“…PHA II is an autosomal-dominant disease featured by hypertension and hyperkalemia (5,6). A recent genetic study reported that mutations of WNK1 and WNK4 cause PHA II (6).…”

Section: Discussionmentioning

confidence: 99%

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

Lazrak

Liu

Huang³

2006

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

160

207

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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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“…PHA II is an autosomal-dominant disease featured by hypertension and hyperkalemia (5,6). A recent genetic study reported that mutations of WNK1 and WNK4 cause PHA II (6).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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.

160

207

View full text Add to dashboard Cite

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“…These cotransporters have recently gained attention in the field of neuroscience, as they facilitate neuronal response to gamma-aminobutyric acid and glycine (Mercado et al, 2004). Furthermore, several members of the cation-chloride co-transporter family are involved in hereditary diseases, such as Gitelman's, Bartter's, Gordon's and Andermann's syndromes, and have shown associations with bipolar disorder (Bianchetti et al, 1992;Dupre et al, 2003;Filteau et al, 1991;Gamba, 2005;Gitelman et al, 1966;Gordon, 1986;Howard et al, 2002bHoward et al, , 2003Meyer et al, 2005;Uyanik et al, 2006). The crucial role of cation co-transporters for neuronal development is also supported by animal studies in which knockout mice for cation-chloride co-transporters display a plethora of symptoms such as deafness, locomotor deficits, severe central and peripheral neurodegeneration, and sensorimotor gating defects (Boettger et al, 2002(Boettger et al, , 2003Hubner et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Functional Analysis of a Potassium-Chloride Co-Transporter 3 (SLC12A6) Promoter Polymorphism Leading to an Additional DNA Methylation Site

Moser

Ekawardhani

Kumsta

et al. 2008

Neuropsychopharmacol

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The human potassium-chloride co-transporter 3 (KCC3, SLC12A6) is involved in cell proliferation and in electro-neutral movement of ions across the cell membrane. The gene (SLC12A6) is located on chromosome 15q14, a region that has previously shown linkage with bipolar disorder, schizophrenia, rolandic epilepsy, idiopathic generalized epilepsy, autism and attention deficit/hyperactivity disorder. Furthermore, recessively inherited mutations of SLC12A6 cause Andermann syndrome, characterized by agenesis of the corpus callosum, which is associated with peripheral neuropathy and psychoses. Recently, we have demonstrated the association of two G/A promoter polymorphisms of SLC12A6 with bipolar disorder in a case-control study, and familial segregation of the rare variants as well as a trend toward association with schizophrenia. To investigate functional consequences of these polymorphisms, lymphocyte DNA was extracted, bisulfite modified, and subsequently sequenced. To investigate SLC12A6 promoter activity, various promoter constructs were generated and analyzed by luciferase reporter gene assays. We provide evidence that the G-allele showed a significant reduction of reporter gene expression. In human lymphocytes, the allele harboring the rare upstream G nucleotide was found to be methylated at the adjacent C position, possibly accountable for tissue-specific reduction in gene expression in vivo. Here we demonstrate functionality of an SNP associated with psychiatric disease and our results may represent a functional link between genetic variation and an epigenetic modification.

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“…Mutations of WNK1 and WNK4 are responsible for pseudohypoaldosteronism type II (PHAІІ), characterized by hypertension, hyperkalemia, and metabolic acidosis. 1,2 The disease mutation in WNK1 or WNK4 kinase resulting in hyperkalemia suggests a role of WNK in potassium handling in renal distal nephron, which contains two major potassium channels, renal outer medullary K + channels (ROMK) and Big K (BK) channels. 3,4 WNK4 inhibits ROMK channel activity and its surface expression, whereas WNK4 disease mutant enhances its inhibitory effect on ROMK.…”

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confidence: 99%

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

Liu

Song

Shi

et al. 2015

Journal of the American Society of Nephrology

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With no lysine (WNK) kinases are members of the serine/threonine kinase family. We previously showed that WNK4 inhibits renal large-conductance Ca 2+ -activated K + (BK) channel activity by enhancing its degradation through a lysosomal pathway. In this study, we investigated the effect of WNK1 on BK channel activity. In HEK293 cells stably expressing the a subunit of BK (HEK-BKa cells), siRNA-mediated knockdown of WNK1 expression significantly inhibited both BKa channel activity and open probability. Knockdown of WNK1 expression also significantly inhibited BKa protein expression and increased ERK1/2 phosphorylation, whereas overexpression of WNK1 significantly enhanced BKa expression and decreased ERK1/2 phosphorylation in a dose-dependent manner in HEK293 cells. Knockdown of ERK1/2 prevented WNK1 siRNA-mediated inhibition of BKa expression. Similarly, pretreatment of HEK-BKa cells with the lysosomal inhibitor bafilomycin A1 reversed the inhibitory effects of WNK1 siRNA on BKa expression in a dose-dependent manner. Knockdown of WNK1 expression also increased the ubiquitination of BKa channels. Notably, mice fed a high-K + diet for 10 days had significantly higher renal protein expression levels of BKa and WNK1 and lower levels of ERK1/2 phosphorylation compared with mice fed a normal-K + diet. These data suggest that WNK1 enhances BK channel function by reducing ERK1/2 signaling-mediated lysosomal degradation of the channel. With no lysine (WNK) kinase belongs to a family of serine/threonine kinases. Mutations of WNK1 and WNK4 are responsible for pseudohypoaldosteronism type II (PHAІІ), characterized by hypertension, hyperkalemia, and metabolic acidosis. 1,2 The disease mutation in WNK1 or WNK4 kinase resulting in hyperkalemia suggests a role of WNK in potassium handling in renal distal nephron, which contains two major potassium channels, renal outer medullary K + channels (ROMK) and Big K (BK) channels. 3,4 WNK4 inhibits ROMK channel activity and its surface expression, whereas WNK4 disease mutant enhances its inhibitory effect on ROMK. 5 WNK1 also inhibits ROMK activity; however, a kidney-specific form of WNK1 (KS-WNK1) reverses WNK1's effect on ROMK. 6 WNK4 inhibits BK channel activity and protein expression, 7-9 whereas WNK4 disease mutant also enhances its inhibitory effect on BK activity via a ubiquitin-dependent pathway. 9 BK channel (or Maxi K) is a large conductance Ca 2+ and voltage-activated K channel. 10 BK is encoded by the gene slo1 11 and is widely distributed in many different

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Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate.

Cited by 205 publications

References 46 publications

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

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

Functional Analysis of a Potassium-Chloride Co-Transporter 3 (SLC12A6) Promoter Polymorphism Leading to an Additional DNA Methylation Site

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

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