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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
Author(s) -
Chang ChizTzung,
Bens Marcelle,
Hummler Edith,
Boulkroun Sheerazed,
Schild Laurent,
Teulon Jacques,
Rossier Bernard C.,
Vandewalle Alain
Publication year - 2005
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2004.077933
Subject(s) - amiloride , epithelial sodium channel , vasopressin , apical membrane , endocrinology , medicine , chemistry , microbiology and biotechnology , arginine , mutant , sodium , biology , biochemistry , amino acid , membrane , gene , organic chemistry
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 ( I sc ) 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 R 566 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) I sc , reflecting ENaC‐dependent Na + absorption. Short‐term incubation with dDAVP caused a rapid and significant increase (∼2‐fold) in Ams I sc 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. I sc 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.