Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit

Publication: Research - peer-reviewJournal article


  • Romain Perrier
    Romain Perrier
  • Emilie Boscardin
    Emilie BoscardinDenmark
  • Sumedha Malsure
    Sumedha Malsure
  • Chloé Sergi
    Chloé Sergi
  • Marc P Maillard
    Marc P MaillardDenmark
  • Johannes Loffing
    Johannes Loffing
  • Dominique Cueni Loffing
    Dominique Cueni LoffingDenmark
  • Mads Vaarby Sørensen
  • Robert Koesters
    Robert KoestersDenmark
  • Bernard C Rossier
    Bernard C Rossier
  • Simona Frateschi
    Simona FrateschiDenmark
  • Edith Hummler
    Edith Hummler

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.

Original languageEnglish
JournalAmerican Society of Nephrology. Journal
Issue number8
Pages (from-to)2309-2318
Number of pages10
StatePublished - 2016

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