Nedd4-2 modulates renal Na+-Cl- cotransporter via the aldosterone-SGK1-Nedd4-2 pathway.

Details

Serval ID
serval:BIB_C55A6EC97B43
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Nedd4-2 modulates renal Na+-Cl- cotransporter via the aldosterone-SGK1-Nedd4-2 pathway.
Journal
Journal of the American Society of Nephrology
Author(s)
Arroyo J.P., Lagnaz D., Ronzaud C., Vázquez N., Ko B.S., Moddes L., Ruffieux-Daidié D., Hausel P., Koesters R., Yang B., Stokes J.B., Hoover R.S., Gamba G., Staub O.
ISSN
1533-3450 (Electronic)
ISSN-L
1046-6673
Publication state
Published
Issued date
2011
Volume
22
Number
9
Pages
1707-1719
Language
english
Abstract
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.
Keywords
11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism, Aldosterone/metabolism, Animals, Down-Regulation, Endosomal Sorting Complexes Required for Transport/metabolism, HEK293 Cells, Humans, Immediate-Early Proteins/metabolism, Kidney Tubules, Distal/enzymology, Mice, Mice, Knockout, Phosphorylation, Protein-Serine-Threonine Kinases/metabolism, Signal Transduction, Sodium Chloride Symporters/metabolism, Ubiquitin-Protein Ligases/metabolism, Ubiquitination, Xenopus laevis
Pubmed
Web of science
Open Access
Yes
Create date
02/11/2011 10:05
Last modification date
20/10/2020 10:12
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