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Physiological regulation of ENaC in the aldosterone‐sensitive distal nephron by a local endothelin system
Author(s) -
Bugaj Vladislav,
Pochynyuk Oleh,
Kohan Donald E,
Stockand James D
Publication year - 2010
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.24.1_supplement.611.11
Subject(s) - epithelial sodium channel , medicine , endocrinology , endothelin receptor , chemistry , receptor , natriuresis , aldosterone , endothelin 1 , kidney , biology , sodium , organic chemistry
We used patch‐clamp electrophysiology to investigate regulation of the epithelial Na + channel (ENaC) by endothelin‐1 (ET‐1) in isolated, split‐open collecting ducts (CD) from wild type (wt) mice and mice with CD‐specific deletion of ET‐1 (CD ET‐1 −/−) and the ETB receptor (CD ETB −/−). Resting ENaC activity was significantly higher in CD ET‐1 −/− and CD ETB −/− mice compared to wt mice. Moreover, exogenous ET‐1 rapidly and significantly decreases ENaC open probability (P o ) in wt and CD ET‐1 −/− but not CD ETB −/− mice. ET‐1 decreases ENaC activity through basolateral membrane ETB receptors. ET‐1 activates src family tyrosine kinases and their downstream MAPK1/2 effector cascade to modulate ENaC. In wt mice, ENaC activity is related inversely to dietary salt intake. This relation is retained but muted in CD ETB −/− mice with these animals requiring higher dietary Na + intake to achieve the same level of ENaC suppression. We conclude that ENaC activity in mammalian principal cells is decreased in a physiologically relevant manner by activation of a local CD endothelin system where ET‐1 through ETB receptors tempers channel activity, at least in part, through src/MAPK1/2 signaling. These findings provide a mechanism for the natriuresis observed in‐vivo in response to ET‐1, as well as, the salt‐sensitive hypertension caused by disrupting the collecting duct endothelin system.