title: Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit.
abstract: Systemic pseudohypoaldosteronism type 1 (PHA-1) is a severe salt-losing syndrome caused by loss-of-function mutations of the amiloride-sensitive epithelial sodium channel (ENaC) and characterized by neonatal life-threatening hypovolemia and hyperkalemia. The very high plasma aldosterone levels detected under hypovolemic or hyperkalemic challenge can lead to increased or decreased sodium reabsorption, respectively, through the Na(+)/Cl(-) cotransporter (NCC). However, the role of ENaC deficiency remains incompletely defined, because constitutive inactivation of individual ENaC subunits is neonatally lethal in mice. We generated adult inducible nephron-specific αENaC-knockout mice (Scnn1a(Pax8/LC1)) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1. Compared with control mice fed a regular-salt diet, knockout mice fed a regular-salt diet exhibited downregulated expression and phosphorylation of NCC protein, despite high plasma aldosterone levels. In knockout mice fed a high-sodium and reduced-potassium diet (rescue diet), although plasma aldosterone levels remained significantly increased, NCC expression returned to control levels, and body weight, plasma and urinary electrolyte concentrations, and excretion normalized. Finally, shift to a regular diet after the rescue diet reinstated the symptoms of severe PHA-1 syndrome and significantly reduced NCC phosphorylation. In conclusion, lack of ENaC-mediated sodium transport along the nephron cannot be compensated for by other sodium channels and/or transporters, only by a high-sodium and reduced-potassium diet. We further conclude that hyperkalemia becomes the determining factor in regulating NCC activity, regardless of sodium loss, in the ENaC-mediated salt-losing PHA-1 phenotype.
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
authors.forename: Romain
authors.initials: R
authors.lastname: Perrier
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland; Swiss National Center of Competence in Research "Kidney.CH", Zurich, Switzerland;
authors.forename: Emilie
authors.initials: E
authors.lastname: Boscardin
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
authors.forename: Sumedha
authors.initials: S
authors.lastname: Malsure
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland;
authors.forename: Chloé
authors.initials: C
authors.lastname: Sergi
authors.affiliation: Service of Nephrology Department, University Hospital of Lausanne, Lausanne, Switzerland;
authors.forename: Marc P
authors.initials: MP
authors.lastname: Maillard
authors.affiliation: Swiss National Center of Competence in Research "Kidney.CH", Zurich, Switzerland; Institute of Anatomy, University of Zurich, Zurich, Switzerland; and.
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.affiliation: Swiss National Center of Competence in Research "Kidney.CH", Zurich, Switzerland; Institute of Anatomy, University of Zurich, Zurich, Switzerland; and.
authors.forename: Dominique
authors.initials: D
authors.lastname: Loffing-Cueni
authors.affiliation: Swiss National Center of Competence in Research "Kidney.CH", Zurich, Switzerland; Institute of Anatomy, University of Zurich, Zurich, Switzerland; and.
authors.forename: Mads Vaarby
authors.initials: MV
authors.lastname: Sørensen
authors.affiliation: Department of Nephrology, Hôpital Tenon, Université Pierre et Marie Curie, Paris, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Koesters
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland; Edith.Hummler@unil.ch Simona.Frateschi@unil.ch.
authors.forename: Bernard C
authors.initials: BC
authors.lastname: Rossier
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland; Swiss National Center of Competence in Research "Kidney.CH", Zurich, Switzerland;
authors.forename: Simona
authors.initials: S
authors.lastname: Frateschi
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland; Swiss National Center of Competence in Research "Kidney.CH", Zurich, Switzerland; Edith.Hummler@unil.ch Simona.Frateschi@unil.ch.
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
mesh_terms: D000818:Animals; D053503:Epithelial Sodium Channels / Q000235:genetics*; D006947:Hyperkalemia / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009399:Nephrons; D011546:Pseudohypoaldosteronism / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D053503:Epithelial Sodium Channels
keywords: ENaC; aldosterone; transgenic mouse