Renal tubular SGK1 deficiency causes impaired K+ excretion via loss of regulation of NEDD4-2/WNK1 and ENaC.

Détails

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Etat: Public
Version: Author's accepted manuscript
ID Serval
serval:BIB_C34743F0B828
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Renal tubular SGK1 deficiency causes impaired K+ excretion via loss of regulation of NEDD4-2/WNK1 and ENaC.
Périodique
American journal of physiology. Renal physiology
Auteur(s)
Al-Qusairi L., Basquin D., Roy A., Stifanelli M., Rajaram R.D., Debonneville A., Nita I., Maillard M., Loffing J., Subramanya A.R., Staub O.
ISSN
1522-1466 (Electronic)
ISSN-L
1522-1466
Statut éditorial
Publié
Date de publication
01/08/2016
Peer-reviewed
Oui
Volume
311
Numéro
2
Pages
F330-42
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
The stimulation of postprandial K(+) clearance involves aldosterone-independent and -dependent mechanisms. In this context, serum- and glucocorticoid-induced kinase (SGK)1, a ubiquitously expressed kinase, is one of the primary aldosterone-induced proteins in the aldosterone-sensitive distal nephron. Germline inactivation of SGK1 suggests that this kinase is fundamental for K(+) excretion under conditions of K(+) load, but the specific role of renal SGK1 remains elusive. To avoid compensatory mechanisms that may occur during nephrogenesis, we used inducible, nephron-specific Sgk1(Pax8/LC1) mice to assess the role of renal tubular SGK1 in K(+) regulation. Under a standard diet, these animals exhibited normal K(+) handling. When challenged by a high-K(+) diet, they developed severe hyperkalemia accompanied by a defect in K(+) excretion. Molecular analysis revealed reduced neural precursor cell expressed developmentally downregulated protein (NEDD)4-2 phosphorylation and total expression. γ-Epithelial Na(+) channel (ENaC) expression and α/γENaC proteolytic processing were also decreased in mutant mice. Moreover, with no lysine kinase (WNK)1, which displayed in control mice punctuate staining in the distal convoluted tubule and diffuse distribution in the connecting tubule/cortical colleting duct, was diffused in the distal convoluted tubule and less expressed in the connecting tubule/collecting duct of Sgk(Pax8/LC1) mice. Moreover, Ste20-related proline/alanine-rich kinase phosphorylation, and Na(+)-Cl(-) cotransporter phosphorylation/apical localization were reduced in mutant mice. Consistent with the altered WNK1 expression, increased renal outer medullary K(+) channel apical localization was observed. In conclusion, our data suggest that renal tubular SGK1 is important in the regulation of K(+) excretion via the control of NEDD4-2, WNK1, and ENaC.

Mots-clé
Amino Acid Sequence, Animals, Antibodies, Blocking/pharmacology, Diet, Endosomal Sorting Complexes Required for Transport/metabolism, Epithelial Sodium Channels/metabolism, Gene Expression Regulation, Immediate-Early Proteins/deficiency, Immediate-Early Proteins/genetics, Kidney Tubules/metabolism, Male, Mice, Mice, Knockout, Minor Histocompatibility Antigens/metabolism, Potassium/urine, Potassium Channels, Inwardly Rectifying/antagonists & inhibitors, Potassium Channels, Inwardly Rectifying/immunology, Potassium, Dietary/pharmacology, Protein-Serine-Threonine Kinases/deficiency, Protein-Serine-Threonine Kinases/genetics, Protein-Serine-Threonine Kinases/metabolism, Ubiquitin-Protein Ligases/metabolism, aldosterone, epithelial Na+ channel, epithelial transport, neural precursor cell expressed developmentally downregulated protein 4-2, phosphorylation, potassium, serum- and glucocorticoid-induced kinase 1, ubiquitylation, with no lysine kinase 1
Pubmed
Web of science
Création de la notice
09/04/2016 16:31
Dernière modification de la notice
20/08/2019 16:38
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