The E3 ubiquitin-protein ligase Nedd4-2 regulates the sodium chloride cotransporter NCC but is not required for a potassium-induced reduction of NCC expression.

Autor:	Rosenbaek LL; Department of Biomedicine, Aarhus University, Aarhus, Denmark.; Leducq Foundation Potassium in Hypertension International Network, Massachusetts, United States., Petrillo F; Department of Biomedicine, Aarhus University, Aarhus, Denmark., van Bemmelen MX; Leducq Foundation Potassium in Hypertension International Network, Massachusetts, United States.; Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland., Staub O; Leducq Foundation Potassium in Hypertension International Network, Massachusetts, United States.; Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland., Murali SK; Department of Biomedicine, Aarhus University, Aarhus, Denmark.; Leducq Foundation Potassium in Hypertension International Network, Massachusetts, United States.; Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria., Fenton RA; Department of Biomedicine, Aarhus University, Aarhus, Denmark.; Leducq Foundation Potassium in Hypertension International Network, Massachusetts, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in physiology [Front Physiol] 2022 Sep 07; Vol. 13, pp. 971251. Date of Electronic Publication: 2022 Sep 07 (Print Publication: 2022).
DOI:	10.3389/fphys.2022.971251
Abstrakt:	Na + and K + balance is influenced by the activity of the sodium chloride cotransporter NCC in the distal convoluted tubule. NCC activity and abundance are reduced by high extracellular K + . The E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-2 (Nedd4-2) has been proposed as a modulator of NCC abundance. Here, we examined the functional role of Nedd4-2 on NCC regulation and whether Nedd4-2 is important for the effects of high extracellular K + on NCC. Total and plasma membrane levels of ubiquitylated NCC were lower in NCC-expressing MDCKI cells after Nedd4-2 deletion. NCC and phosphorylated NCC (pT58-NCC) levels were higher after Nedd4-2 deletion, and NCC levels on the plasma membrane were elevated. No significant changes were seen after Nedd4-2 knockdown in the levels of SPAK and phosphorylated SPAK (pS373-SPAK), the major NCC regulatory kinase. Nedd4-2 deficiency had no effect on the internalization rate of NCC from the plasma membrane, but NCC protein half-life was increased. In ex vivo experiments with kidney tubule suspensions from Nedd4-2 knockout (KO) mice, high K + reduced total and pT58-NCC regardless of genotype. We conclude that Nedd4-2 is involved in ubiquitylation of NCC and modulating its plasma membrane levels and degradation. However, Nedd4-2 does not appear to be important for K + induced reductions in NCC abundance. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Rosenbaek, Petrillo, van Bemmelen, Staub, Murali and Fenton.)
Databáze:	MEDLINE
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