title: Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion.
abstract: 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 (Nedd4LPax8/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 inNedd4LPax8/LC1mice, 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 inNedd4LPax8/LC1mice, 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.|National Centre of Competence in Research "Kidney.ch", Zurich, Switzerland.
authors.forename: Lama
authors.initials: L
authors.lastname: Al-Qusairi
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.|National Centre of Competence in Research "Kidney.ch", Zurich, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Basquin
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine and VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; and.
authors.forename: Ankita
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.|National Centre of Competence in Research "Kidney.ch", Zurich, Switzerland.
authors.forename: Renuga Devi
authors.initials: RD
authors.lastname: Rajaram
authors.affiliation: Service of Nephrology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Maillard
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine and VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; and olivier.staub@unil.ch ars129@pitt.edu.
authors.forename: Arohan R
authors.initials: AR
authors.lastname: Subramanya
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland; olivier.staub@unil.ch ars129@pitt.edu.|National Centre of Competence in Research "Kidney.ch", Zurich, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Staub
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D056827:Endosomal Sorting Complexes Required for Transport / Q000502:physiology*; D007008:Hypokalemia / Q000503:physiopathology*; D007668:Kidney / Q000503:physiopathology; D007686:Kidney Tubules, Distal / Q000201:enzymology*; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: ENaC; K channels; ion transport; signaling