Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit.

Détails

Ressource 1Télécharger: 5_26701978_Postprint.pdf (12960.87 [Ko])
Etat: Public
Version: Author's accepted manuscript
ID Serval
serval:BIB_F75A14309BCC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit.
Périodique
Journal of the American Society of Nephrology
Auteur(s)
Perrier R., Boscardin E., Malsure S., Sergi C., Maillard M.P., Loffing J., Loffing-Cueni D., Sørensen M.V., Koesters R., Rossier B.C., Frateschi S., Hummler E.
ISSN
1533-3450 (Electronic)
ISSN-L
1046-6673
Statut éditorial
Publié
Date de publication
08/2016
Peer-reviewed
Oui
Volume
27
Numéro
8
Pages
2309-2318
Langue
anglais
Notes
Publication types: Journal Article Publication Status: ppublish
Résumé
Systemic pseudohypoaldosteronism type 1 (PHA-1) is a severe salt-losing syndrome caused by loss-of-function mutations of the amiloride-sensitive epithelial sodium channel (ENaC) and characterized by neonatal life-threatening hypovolemia and hyperkalemia. The very high plasma aldosterone levels detected under hypovolemic or hyperkalemic challenge can lead to increased or decreased sodium reabsorption, respectively, through the Na(+)/Cl(-) cotransporter (NCC). However, the role of ENaC deficiency remains incompletely defined, because constitutive inactivation of individual ENaC subunits is neonatally lethal in mice. We generated adult inducible nephron-specific αENaC-knockout mice (Scnn1a(Pax8/LC1)) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1. Compared with control mice fed a regular-salt diet, knockout mice fed a regular-salt diet exhibited downregulated expression and phosphorylation of NCC protein, despite high plasma aldosterone levels. In knockout mice fed a high-sodium and reduced-potassium diet (rescue diet), although plasma aldosterone levels remained significantly increased, NCC expression returned to control levels, and body weight, plasma and urinary electrolyte concentrations, and excretion normalized. Finally, shift to a regular diet after the rescue diet reinstated the symptoms of severe PHA-1 syndrome and significantly reduced NCC phosphorylation. In conclusion, lack of ENaC-mediated sodium transport along the nephron cannot be compensated for by other sodium channels and/or transporters, only by a high-sodium and reduced-potassium diet. We further conclude that hyperkalemia becomes the determining factor in regulating NCC activity, regardless of sodium loss, in the ENaC-mediated salt-losing PHA-1 phenotype.
Pubmed
Open Access
Oui
Création de la notice
18/01/2016 11:29
Dernière modification de la notice
20/08/2019 16:23
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