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1 INSERM U478, Faculté de Médecine Xavier Bichat, BP 416, 75870 Paris, France
2
Institut de Pharmacologie et de Toxicologie, Université de Lausanne, CH-1005 Lausanne, Switzerland
3
CNRS-FRE 2468, Institut des Cordeliers, 75270 Paris, France
Liddle's syndrome is a genetic form of hypertension linked to Na+ retention caused by activating mutations in the COOH terminus of the ß or 
subunit of the epithelial sodium channel (ENaC). In this study, we used the short-circuit current (Isc) method to investigate the effects of deamino-8-D-arginine vasopressin (dDAVP) on Na+ and Cl– fluxes in primary cultures of cortical collecting ducts (CCDs) microdissected from the kidneys of mice with Liddle's syndrome carrying a stop codon mutation, corresponding to the ß-ENaC R566 stop mutation (L) found in the original pedigree. Compared to wild-type (+/+) CCD cells, untreated L/+ and L/L CCD cells exhibited 2.7- and 4.2-fold increases, respectively, in amiloride-sensitive (Ams) Isc, reflecting ENaC-dependent Na+ absorption. Short-term incubation with dDAVP caused a rapid and significant increase (
2-fold) in Ams Isc in +/+, but not in L/+ or L/L CCD cells. In sharp contrast, dDAVP induced a greater increase in 5-nitro-2-(3-phenylpropamino)benzoate (NPPB)-inhibited apical Cl– currents in amiloride-treated L/L and L/+ cells than in their +/+ counterparts. Isc recordings performed under apical ion substituted conditions revealed that the dDAVP-stimulated apical secretion of Cl–, which was absent in cultured CCDs lacking CFTR, was 1.8-fold greater in L/+ and 3.7-fold greater in L/L CCD cells than in their +/+ CCD counterparts. After the basal membrane had been permeabilized with nystatin and a basal-to-apical Cl– gradient had been imposed, dDAVP also stimulated larger Cl– currents across L/L and L/+ CCD layers than +/+ CCD layers. These findings demonstrate that vasopressin stimulates greater apical CFTR Cl– conductance in the renal CCD cells of mice with Liddle's syndrome than in wild-type mice. This effect could contribute to the enhanced NaCl reabsorption observed in the distal nephron of patients with Liddle's syndrome.
(Received 22 October 2004;
accepted after revision 25 October 2004;
first published online 28 October 2004)
Corresponding author A. Vandewalle: INSERM U478, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, BP 416, 75870 Paris Cedex 18, France. Email: vandewal{at}bichat.inserm.fr
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