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Vasopressin-stimulated CFTR Cl− currents are increased in the renal collecting duct cells of a mouse model of Liddle's syndrome

By Chiz-Tzung Chang, Marcelle Bens, Edith Hummler, Sheerazed Boulkroun, Laurent Schild, Jacques Teulon, Bernard C Rossier and Alain Vandewalle


Liddle's syndrome is a genetic form of hypertension linked to Na+ retention caused by activating mutations in the COOH terminus of the β or γ 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 β-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

Topics: Cell Physiology
Publisher: Blackwell Science Inc
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Provided by: PubMed Central
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