| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Perrier, Romain Boscardin, Emilie Malsure, Sumedha Sergi, Chloé Maillard, Marc P. Loffing, Johannes Loffing-Cueni, Dominique Sørensen, Mads Vaarby Koesters, Robert Rossier, Bernard C. Frateschi, Simona Hummler, Edith |
| Description |
Author Affiliation: Perrier R ( Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland); Boscardin E ( Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland); Malsure S ( Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland); Sergi C ( Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland); Maillard MP ( Service of Nephrology Department, University Hospital of Lausanne, Lausanne, Switzerland); Loffing J ( Swiss National Center of Competence in Research 'Kidney.CH', Zurich, Switzerland); Loffing-Cueni D ( Swiss National Center of Competence in Research 'Kidney.CH', Zurich, Switzerland); Sørensen MV ( Swiss National Center of Competence in Research 'Kidney.CH', Zurich, Switzerland); Koesters R ( Department of Nephrology, Hôpital Tenon, Université Pierre et Marie Curie, Paris, France.); Rossier BC ( Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland); Frateschi S ( Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland); Hummler E ( Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland) |
| 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 ENaC-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. |
| File Format |
HTM / HTML |
| ISSN |
10466673 |
| e-ISSN |
15333450 |
| Journal |
Journal of the American Society of Nephrology |
| Issue Number |
8 |
| Volume Number |
27 |
| Language |
English |
| Publisher |
American Society of Nephrology |
| Publisher Date |
2016-08-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Discipline Nephrology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Nephrology |
