Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion.

Détails

ID Serval
serval:BIB_43B4FD9B28CF
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion.
Périodique
Journal of the American Society of Nephrology
Auteur(s)
Al-Qusairi L., Basquin D., Roy A., Rajaram R.D., Maillard M.P., Subramanya A.R., Staub O.
ISSN
1533-3450 (Electronic)
ISSN-L
1046-6673
Statut éditorial
Publié
Date de publication
08/2017
Peer-reviewed
Oui
Volume
28
Numéro
8
Pages
2431-2442
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Adaptation of the organism to potassium (K(+)) deficiency requires precise coordination among organs involved in K(+) homeostasis, including muscle, liver, and kidney. How the latter performs functional and molecular changes to ensure K(+) retention is not well understood. Here, we investigated the role of ubiquitin-protein ligase NEDD4-2, which negatively regulates the epithelial sodium channel (ENaC), Na(+)/Cl(-) cotransporter (NCC), and with no-lysine-kinase 1 (WNK1). After dietary K(+) restriction for 2 weeks, compared with control littermates, inducible renal tubular NEDD4-2 knockout (Nedd4L(Pax8/LC1) ) mice exhibited severe hypokalemia and urinary K(+) wasting. Notably, expression of the ROMK K(+) channel did not change in the distal convoluted tubule and decreased slightly in the cortical/medullary collecting duct, whereas BK channel abundance increased in principal cells of the connecting tubule/collecting ducts. However, K(+) restriction also enhanced ENaC expression in Nedd4L(Pax8/LC1) mice, and treatment with the ENaC inhibitor, benzamil, reversed excessive K(+) wasting. Moreover, K(+) restriction increased WNK1 and WNK4 expression and enhanced SPAK-mediated NCC phosphorylation in Nedd4L(Pax8/LC1) mice, with no change in total NCC. We propose a mechanism in which NEDD4-2 deficiency exacerbates hypokalemia during dietary K(+) restriction primarily through direct upregulation of ENaC, whereas increased BK channel expression has a less significant role. These changes outweigh the compensatory antikaliuretic effects of diminished ROMK expression, increased NCC phosphorylation, and enhanced WNK pathway activity in the distal convoluted tubule. Thus, NEDD4-2 has a crucial role in K(+) conservation through direct and indirect effects on ENaC, distal nephron K(+) channels, and WNK signaling.

Mots-clé
Adaptation, Physiological, Animals, Endosomal Sorting Complexes Required for Transport/physiology, Hypokalemia/physiopathology, Kidney/physiopathology, Kidney Tubules, Distal/enzymology, Mice, Time Factors, Ubiquitin-Protein Ligases/physiology, ENaC, K channels, ion transport, signaling
Pubmed
Web of science
Open Access
Oui
Création de la notice
21/03/2017 18:02
Dernière modification de la notice
20/08/2019 13:47
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