Premium
Regulation of ENaC in the rat collecting duct by endothelin‐1
Author(s) -
Pochynyuk Oleh,
Bugaj Vladislav,
Stockand James D
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1215.7
Subject(s) - epithelial sodium channel , endothelin receptor , medicine , endocrinology , reabsorption , chemistry , endothelin 1 , receptor , microbiology and biotechnology , biology , kidney , sodium , organic chemistry
The epithelial sodium channel (ENaC) plays a critical role in setting systemic salt and water balance and thus, blood pressure. Activity of this channel is limiting for Na + reabsorption at the renal collecting duct. Cell signaling in response to endothelin (ET‐1) via the endothelin B receptor decreases ENaC activity in heterologous expression systems. Moreover, as shown by the Kohan laboratory, targeted deletion of ET‐1 and the endothelin B receptor in mouse collecting duct causes hypertension associated with sodium retention. This hypertension is exacerbated by a high sodium diet implicating dysfunctional ENaC regulation. Thus, we test here the hypothesis that ET‐1 modulates ENaC activity in the isolated, split‐open rat collecting duct. In addition, we define the cellular signaling pathway underpinning such regulation in native collecting duct. We find that ET‐1 rapidly decreases ENaCopen probability in the rat collecting duct. As in model cells, pretreatment with a selective Src family kinase inhibitor (PP2) but not its inactive analogue (PP3), blocked ET‐1 action on ENaC. Moreover, inhibition of the endothelin receptor blocked ET‐1 action. Following ET‐1 treatment, ENaC remains in the membrane in a closed/inactive state for increases in apical PI(4,5)P 2 levels surmounts endothelin‐dependent inhibition. We conclude that ET‐1 through endothelin B coupled to Src tyrosine kinases decreased ENaC activity in native collecting duct cells by rapidly decreasing channel open probability. These results demonstrate that ET‐1 signaling through Src via the endothelin receptor is a major negative regulator of ENaC activity in native renal epithelialcells.