title: Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure.
abstract: Ubiquitylation plays an important role in the control of Na⁺ homeostasis by the kidney. It is well established that the epithelial Na⁺ channel ENaC is regulated by the ubiquitin-protein ligase NEDD4-2, limiting ENaC cell surface expression and activity. Ubiquitylation can be reversed by the action of deubiquitylating enzymes (DUBs). One such DUB, USP2-45, was identified previously as an aldosterone-induced protein in the kidney and is also a circadian output gene. In heterologous expression systems, USP2-45 binds to ENaC, deubiquitylates it, and enhances channel density and activity at the cell surface. Because the role of USP2-45 in renal Na⁺ transport had not been studied in vivo, we investigated here the effect of Usp2 gene inactivation in this process. We demonstrate first that USP2-45 protein has a rhythmic expression with a peak at ZT12. Usp2-KO mice did not show any differences from wild-type littermates with respect to the diurnal control of Na⁺ or K⁺ urinary excretion and plasma levels either on a standard diet or after acute and chronic changes to low- and high-Na⁺ diets, respectively. Moreover, they had similar aldosterone levels on either a low- or high-Na⁺ diet. Blood pressure measurements using telemetry did not reveal variations compared with control mice. Usp2-KO mice did not display alterations in expression of genes involved in sodium homeostasis or the ubiquitin system, as evidenced by transcriptome analysis in the kidney. Our data suggest that USP2 does not play a primary role in the control of Na⁺ balance or blood pressure.
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pouly
authors.forename: Anne
authors.initials: A
authors.lastname: Debonneville
authors.forename: Dorothée
authors.initials: D
authors.lastname: Ruffieux-Daidié
authors.forename: Marc
authors.initials: M
authors.lastname: Maillard
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.forename: Olivier
authors.initials: O
authors.lastname: Staub
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure; D018660:Blood Pressure Monitoring, Ambulatory / Q000379:methods; D002940:Circadian Rhythm; D004039:Diet, Sodium-Restricted; D010450:Endopeptidases / Q000172:deficiency* / Q000235:genetics; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017440:Photoperiod; D011188:Potassium / Q000097:blood; D012964:Sodium / Q000097:blood*; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000097:blood; D013686:Telemetry; D013997:Time Factors; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination
chemical_list: D053503:Epithelial Sodium Channels; D017673:Sodium Chloride, Dietary; D000450:Aldosterone; D012964:Sodium; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; C579224:Usp2 protein, mouse; D011188:Potassium
keywords: ENaC; blood pressure; circadian rhythm; deubiquitylation; sodium transport