title: Phenotype resembling Gitelman's syndrome in mice lacking the apical Na+-Cl- cotransporter of the distal convoluted tubule.
abstract: Mutations in the gene encoding the thiazide-sensitive Na+-Cl- cotransporter (NCC) of the distal convoluted tubule cause Gitelman's syndrome, an inherited hypokalemic alkalosis with hypomagnesemia and hypocalciuria. These metabolic abnormalities are secondary to the deficit in NaCl reabsorption, but the underlying mechanisms are unclear. To gain a better understanding of the role of NCC in sodium and fluid volume homeostasis and in the pathogenesis of Gitelman's syndrome, we used gene targeting to prepare an NCC-deficient mouse. Null mutant (Ncc-/-) mice appear healthy and are normal with respect to acid-base balance, plasma electrolyte concentrations, serum aldosterone levels, and blood pressure. Ncc-/- mice retain Na+ as well as wild-type mice when fed a Na+-depleted diet; however, after 2 weeks of Na+ depletion the mean arterial blood pressure of Ncc-/- mice was significantly lower than that of wild-type mice. In addition, Ncc-/- mice exhibited increased renin mRNA levels in kidney, hypomagnesemia and hypocalciuria, and morphological changes in the distal convoluted tubule. These data indicate that the loss of NCC activity in the mouse causes only subtle perturbations of sodium and fluid volume homeostasis, but renal handling of Mg2+ and Ca2+ are altered, as observed in Gitelman's syndrome.
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, the University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Schultheis
authors.forename: J N
authors.initials: JN
authors.lastname: Lorenz
authors.forename: P
authors.initials: P
authors.lastname: Meneton
authors.forename: M L
authors.initials: ML
authors.lastname: Nieman
authors.forename: T M
authors.initials: TM
authors.lastname: Riddle
authors.forename: M
authors.initials: M
authors.lastname: Flagella
authors.forename: J J
authors.initials: JJ
authors.lastname: Duffy
authors.forename: T
authors.initials: T
authors.lastname: Doetschman
authors.forename: M L
authors.initials: ML
authors.lastname: Miller
authors.forename: G E
authors.initials: GE
authors.lastname: Shull
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D001477:Bartter Syndrome / Q000235:genetics* / Q000652:urine; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D017931:DNA Primers; D004195:Disease Models, Animal; D007686:Kidney Tubules, Distal / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D010641:Phenotype; D011188:Potassium / Q000652:urine; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000235:genetics; D012964:Sodium / Q000652:urine; D049992:Sodium Chloride Symporters; D027981:Symporters
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D012333:RNA, Messenger; D049992:Sodium Chloride Symporters; D027981:Symporters; D000450:Aldosterone; D012964:Sodium; D012083:Renin; D011188:Potassium