Disturbances of Na/K Balance

Bonny, Olivier; Rossier, Bernard C.

doi:10.1097/01.asn.0000028641.59030.b2

Cited by 88 publications

(32 citation statements)

References 148 publications

(79 reference statements)

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“…How do these results expand understanding of this novel WNK pathway? The FHHt phenotype and usual hyperresponsiveness to thiazide diuretics highlight the importance of DCT in electrolyte balance and BP control (1,5,22). The work above provides some of the first clues as to the role in vivo of WNK1-S, the predominant WNK1 isoform in kidney, and intriguingly shows that strongest WNK1-S and WNK4 expression co-localizes in DCT-CNT, where they may contribute to a mechanism that regulates K ϩ homeostasis and BP.…”

Section: Discussionmentioning

confidence: 85%

“…Mutations in either cause a broadly similar phenotype, suggesting that WNK1 and WNK4 function in a common pathway. Unlike most monogenic disorders that affect BP, which feature reciprocal Na ϩ and K ϩ (and/or H ϩ ) imbalances and share a relationship to the aldosterone pathway (4), FHHt features concurrent NaCl and K ϩ (and/or H ϩ ) retention (1,3,5). This unusual characteristic indicates the existence of a novel "WNK pathway" functioning in normal physiology, which may allow the "independent of aldosterone" regulation of K and Na balance (and extracellular volume) by the kidney, ultimately also maintaining BP within the normal range.…”

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confidence: 99%

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Dietary Electrolyte–Driven Responses in the Renal WNK Kinase Pathway In Vivo

O’Reilly¹,

Marshall²,

MacGillivray³

et al. 2006

Journal of the American Society of Nephrology

111

114

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T he role of WNK1 and WNK4 in control of electrolyte balance and BP first became apparent with their mutation being associated with familial hyperkalemic hypertension (FHHt; also known as Gordon syndrome and pseudohypoaldosteronism type 2), a human autosomal dominant disorder that features hypertension, hyperkalemia, and acidosis that usually are hyperresponsive to thiazide diuretics (1,2). FHHt can be caused by intronic deletions in WNK1 or missense mutations in WNK4 (3). Mutations in either cause a broadly similar phenotype, suggesting that WNK1 and WNK4 function in a common pathway. Unlike most monogenic disorders that affect BP, which feature reciprocal Na ϩ and K ϩ (and/or H ϩ ) imbalances and share a relationship to the aldosterone pathway (4), FHHt features concurrent NaCl and K ϩ (and/or H ϩ ) retention (1,3,5). This unusual characteristic indicates the existence of a novel "WNK pathway" functioning in normal physiology, which may allow the "independent of aldosterone" regulation of K and Na balance (and extracellular volume) by the kidney, ultimately also maintaining BP within the normal range. The BP-regulatory role of this WNK pathway is conserved in evolution as WNK1ϩ/Ϫ mice are hypotensive (6).Previously, we and others demonstrated that a 5Ј-truncated kinase-deficient isoform (WNK1-S) predominates in kidney (7), this being conserved between human and mouse (7-9). Isoform-specific probes distinguished ubiquitous low-level expression of full-length WNK1-long (WNK1-L) from abundant WNK1-S expression in distal nephron. Recent Xenopus oocyte studies implicate WNK4 in inhibition of NaCl reabsorption by thiazide-sensitive Na ϩ Cl Ϫ co-transporter (NCC) (10,11) and/or Materials and Methods Animal TreatmentAll procedures were carried out under provisions of ethically approved licenses and involved adult, 25-to 30-g, male C57BL/6 mice (Charles River, Margate, UK). Modified electrolyte feeds for mice were obtained from Special Diet Services (Witham, UK). RNA ExtractionAt conclusion of treatments of mice, both kidneys were removed under terminal anesthetic, immediately frozen on dry ice, and stored at Ϫ80°C. Frozen kidneys were fragmented and immediately homogenized in TRIzol Reagent (Invitrogen, Paisley, UK), and total RNA was extracted following the manufacturer's guidelines. Real-Time PCRAssays used ABI PRISM 7900 relative quantification real-time methods (Applied Biosystems, Foster City, CA). PCR was performed in 384-well plates (AB Gene) and used 10-l reactions that contained 5.0 l of TaqMan Master Mix (Applied Biosystems), 200 nM of each primer, 5 nM of probe, and 4.5 l of template (1:40 dilution of cDNA synthesized as described previously [7]). PCR conditions involved 95°C for 10 min, then 40 cycles of 95°C for 15 s and 60°C for 60 s. Standard template dilution curves enabled target gene quantification and normalization to the endogenous control TATA-Box Binding Protein (TBP). All group values were calibrated to their control groups.Validation studies using mouse renal RNA established TBP as an excelle...

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Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 99%

Dietary Electrolyte–Driven Responses in the Renal WNK Kinase Pathway In Vivo

O’Reilly¹,

Marshall²,

MacGillivray³

et al. 2006

Journal of the American Society of Nephrology

111

114

View full text Add to dashboard Cite

show abstract

“…Two other mutations with comparable impact on the protein structure, R56X and I68fs, have been published earlier (4,6). The I68fs mutation, if co-expressed with the beta and gamma subunits in Xenopus laevis oocytes, completely abolishes sodium currents (24). Based on the clinical phenotype, the Cys63* mutation is likely to have a comparable impact on ENaC function.…”

Section: Discussionmentioning

confidence: 99%

Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1

Welzel

Akın

Büscher³

et al. 2013

European Journal of Endocrinology

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Background: Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disease caused by mutations in the genes encoding the human mineralocorticoid receptor (MR) or the a (SCNN1A), b (SCNN1B) or g (SCNN1G) subunit of the epithelial Na C channel (ENaC). While autosomal dominant mutation of the MR cause renal PHA1, autosomal recessive mutations of the ENaC lead to systemic PHA1. In the latter, affected children suffer from neonatal onset of multi-organ salt loss and often exhibit cystic fibrosis-like pulmonary symptoms. Objective: We searched for underlying mutations in seven unrelated children with systemic PHA1, all offsprings of healthy consanguineous parents. Methods and results: Amplification of the SCNN1A gene and sequencing of all 13 coding exons unraveled mutations in all of our patients. We found five novel homozygous mutations (c.587_588insC in two patients, c.1342_1343insTACA, c.742delG, c.189COA, c.1361-2AOG) and one known mutation (c.1474COT) leading to truncation of the aENaC protein. All parents were asymptomatic heterozygous carriers of the respective mutations, confirming the autosomal recessive mode of inheritance. Five out of seven patients exhibited pulmonary symptoms in the neonatal period. Conclusion: The a subunit is essential for ENaC function and mutations truncating the pore-forming part of the protein leading to systemic PHA1. Based on current knowledge, the pulmonary phenotype cannot be satisfactorily predicted.

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“…Su acción requiere, a nivel celular, la existencia del receptor mineralocorticoide (RM) y de proteínas transportadoras de sodio denominadas canales epiteliales de sodio (CES), que actúan a nivel apical, donde favorece la reabsorción electrogénica de sodio y la eliminación de potasio hacia la orina. 1,2 El seudohipoaldosteronismo de tipo 1 (PH1) es un síndrome de resistencia mineralocorticoide infrecuente que se caracteriza por pérdida salina, hiponatremia, hiperpotasemia, acidosis metabólica hiperclorémica e hiperaldosteronismo hiperreninémico. Se han identificado formas genéticas autosómicas recesivas (AR) y dominantes (AD), casos esporádicos y un tipo secundario a uropatías e infección urinaria, entre otras causas (Tabla 1).…”

Section: Introductionunclassified

“…Se han identificado formas genéticas autosómicas recesivas (AR) y dominantes (AD), casos esporádicos y un tipo secundario a uropatías e infección urinaria, entre otras causas (Tabla 1). [1][2][3][4][5][6][7] Por lo general, el síndrome se presenta de manera insidiosa, rara vez se manifiesta como una emergencia hidroelectrolítica como lo ejemplifican los casos que se presentan, tres de tipo secundario y uno genético AD.…”

Section: Introductionunclassified

Seudohipoaldosteronismo de tipo 1: una emergencia hidroelectrolítica infrecuente. Comunicación de cuatro casos

Marín¹

2011

Arch Argent Pediat

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RESUMENEl seudohipoaldosteronismo de tipo 1 es un síndrome infrecuente de resistencia a la aldosterona que se manifiesta con pér-dida salina, hiponatremia, hiperpotasemia, acidosis metabólica hiperclorémica e hiperaldosteronismo hiperreninémico. El sín-drome puede ser genético; secundario a uropatías e infección urinaria entre otras causas o presentarse esporádicamente. La pérdida salina puede ser sistémica y grave o localizada a nivel renal, por lo general, con mejor pronóstico. El cuadro clínico se manifiesta predominantemente en los primeros siete meses de vida; un marcado retraso pondoestatural y vómitos recurrentes suelen ser los signos clínicos habituales, rara vez se presenta como una emergencia hidroelectrolítica en forma de shock hipovolémico, arritmias cardíacas hiperpotasémicas y crisis convulsiva por hiponatremia. Se presentan cuatro pacientes que debutaron como una emergencia hidroelectrolítica. Palabras clave: seudohipoaldosteronismo de tipo 1, hiponatremia, hiperpotasemia, aldosterona, infección urinaria. SUMMARYPseudohypoaldosteronism type 1 is a rare syndrome of resistance to aldosterone manifested by salt wasting, hyponatremia, hyperkalemia, hyperchloremic metabolic acidosis, and hiperreninemic hyperaldosteronism. The syndrome may be genetic, secondary to uropathies and urinary tract infection among other causes or it may occur sporadically. The salt wasting may be systemic and severe or localized to the kidney usually with better prognosis. The clinical picture is prevalent in the first seven months of life, failure to thrive and recurrent vomiting are usually the common clinical signs, an electrolyte emergency in the form of hypovolemic shock, hyperkalemic cardiac arrhythmias and hyponatremic seizures is rare. Four patients presenting with an electrolyte emergency are reported INTRODUCCIÓNLa aldosterona es un mineralocorticoide que actúa principalmente en el riñón y secundariamente en colon, pulmón y glándulas sudoríparas, salivales y lagrimales. Su acción requiere, a nivel celular, la existencia del receptor mineralocorticoide (RM) y de proteínas transportadoras de sodio denominadas canales epiteliales de sodio (CES), que actúan a nivel apical, donde favorece la reabsorción electrogénica de sodio y la eliminación de potasio hacia la orina.

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Disturbances of Na/K Balance

Cited by 88 publications

References 148 publications

Dietary Electrolyte–Driven Responses in the Renal WNK Kinase Pathway In Vivo

Dietary Electrolyte–Driven Responses in the Renal WNK Kinase Pathway In Vivo

Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1

Seudohipoaldosteronismo de tipo 1: una emergencia hidroelectrolítica infrecuente. Comunicación de cuatro casos

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