Dysfunction of the epithelial sodium channel expressed in the kidney of a mouse model for Liddle syndrome

J Am Soc Nephrol. 2003 Sep;14(9):2219-28. doi: 10.1097/01.asn.0000080204.65527.e6.


The Liddle syndrome is a dominant form of salt-sensitive hypertension resulting from mutations in the beta or gamma subunit of ENaC. A previous study established a mouse model carrying a premature Stop codon corresponding to the R(566stop) mutation (L) found in the original pedigree that recapitulates to a large extent the human disease. This study investigated the renal Na(+) transport in vivo, ex vivo (intact perfused tubules), and in vitro (primary cultured cortical collecting ducts [CCD]). In vivo, upon 6 to 12 h of salt repletion, after 1 week of low-salt diet, the L/L mice showed a delayed urinary sodium excretion, despite a lower aldosterone secretion as compared with controls. After 6 h salt of repletion, ENaC gamma subunit is rapidly removed from the apical plasma membrane in wild-type mice, whereas it is retained at the apical membrane in L/L mice. Ex vivo, isolated perfused CCD from L/L mice exhibited higher transepithelial potential differences than perfused CCD isolated from +/+ mice. In vitro, confluent primary cultures of CCD microdissected from L/L kidneys grown on permeable filters exhibited significant lower transepithelial electrical resistance and higher negative potential differences than their cultured L/+ and +/+ CCD counterparts. The equivalent short-circuit current (I(eq)) and the amiloride-sensitive I(eq) was approximately twofold higher in cultured L/L CCD than in +/+ CCD. Aldosterone (5 x 10(-7)M for 3 h) further increased I(eq) from cultured L/L CCD. Thus, this study brings three independent lines of evidence for the constitutive hyperactivity of ENaC in CCD from mice harboring the Liddle mutation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aldosterone / urine
  • Animals
  • Body Weight
  • Culture Techniques
  • Disease Models, Animal
  • Electrolytes / urine
  • Epithelium / metabolism
  • Kidney Tubules, Collecting / metabolism*
  • Mice
  • Mice, Transgenic
  • Pseudohypoaldosteronism / metabolism*
  • RNA, Messenger / metabolism
  • Sodium Channels / metabolism*
  • Syndrome


  • Electrolytes
  • RNA, Messenger
  • Sodium Channels
  • Aldosterone