title: Dysfunction of the epithelial sodium channel expressed in the kidney of a mouse model for Liddle syndrome.
abstract: 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.
authors.affiliation: Institut de Pharmacologie et de Toxicologie de l'Université, Lausanne, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pradervand
authors.forename: Alain
authors.initials: A
authors.lastname: Vandewalle
authors.forename: Marcelle
authors.initials: M
authors.lastname: Bens
authors.forename: Ivan
authors.initials: I
authors.lastname: Gautschi
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.forename: Edith
authors.initials: E
authors.lastname: Hummler
authors.forename: Laurent
authors.initials: L
authors.lastname: Schild
authors.forename: Bernard C
authors.initials: BC
authors.lastname: Rossier
mesh_terms: D000450:Aldosterone / Q000652:urine; D000818:Animals; D001835:Body Weight; D046508:Culture Techniques; D004195:Disease Models, Animal; D004573:Electrolytes / Q000652:urine; D004848:Epithelium / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011546:Pseudohypoaldosteronism / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D013577:Syndrome
chemical_list: D004573:Electrolytes; D012333:RNA, Messenger; D015222:Sodium Channels; D000450:Aldosterone