Titre
Nedd4-2 modulates renal Na+-Cl- cotransporter via the aldosterone-SGK1-Nedd4-2 pathway.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Auteur(s)
Arroyo, J.P.
Auteure/Auteur
Lagnaz, D.
Auteure/Auteur
Ronzaud, C.
Auteure/Auteur
Vázquez, N.
Auteure/Auteur
Ko, B.S.
Auteure/Auteur
Moddes, L.
Auteure/Auteur
Ruffieux-Daidié, D.
Auteure/Auteur
Hausel, P.
Auteure/Auteur
Koesters, R.
Auteure/Auteur
Yang, B.
Auteure/Auteur
Stokes, J.B.
Auteure/Auteur
Hoover, R.S.
Auteure/Auteur
Gamba, G.
Auteure/Auteur
Staub, O.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1533-3450
Statut éditorial
Publié
Date de publication
2011
Volume
22
Numéro
9
Première page
1707
Dernière page/numéro d’article
1719
Langue
anglais
Résumé
Regulation of renal Na(+) transport is essential for controlling blood pressure, as well as Na(+) and K(+) homeostasis. Aldosterone stimulates Na(+) reabsorption by the Na(+)-Cl(-) cotransporter (NCC) in the distal convoluted tubule (DCT) and by the epithelial Na(+) channel (ENaC) in the late DCT, connecting tubule, and collecting duct. Aldosterone increases ENaC expression by inhibiting the channel's ubiquitylation and degradation; aldosterone promotes serum-glucocorticoid-regulated kinase SGK1-mediated phosphorylation of the ubiquitin-protein ligase Nedd4-2 on serine 328, which prevents the Nedd4-2/ENaC interaction. It is important to note that aldosterone increases NCC protein expression by an unknown post-translational mechanism. Here, we present evidence that Nedd4-2 coimmunoprecipitated with NCC and stimulated NCC ubiquitylation at the surface of transfected HEK293 cells. In Xenopus laevis oocytes, coexpression of NCC with wild-type Nedd4-2, but not its catalytically inactive mutant, strongly decreased NCC activity and surface expression. SGK1 prevented this inhibition in a kinase-dependent manner. Furthermore, deficiency of Nedd4-2 in the renal tubules of mice and in cultured mDCT(15) cells upregulated NCC. In contrast to ENaC, Nedd4-2-mediated inhibition of NCC did not require the PY-like motif of NCC. Moreover, the mutation of Nedd4-2 at either serine 328 or 222 did not affect SGK1 action, and mutation at both sites enhanced Nedd4-2 activity and abolished SGK1-dependent inhibition. Taken together, these results suggest that aldosterone modulates NCC protein expression via a pathway involving SGK1 and Nedd4-2 and provides an explanation for the well-known aldosterone-induced increase in NCC protein expression.
Sujets
PID Serval
serval:BIB_C55A6EC97B43
PMID
Open Access
Oui
Date de création
2011-11-02T09:05:46.581Z
Date de création dans IRIS
2025-05-20T21:44:52Z