Open AccessPurinergic Inhibition of ENaC Produces Aldosterone Escape
Author(s) -
James D. Stockand,
Elena Mironova,
Vladislav Bugaj,
Timo Rieg,
Paul A. Insel,
Volker Vallon,
János Peti-Peterdi,
Oleh Pochynyuk
Publication year - 2010
Publication title -
journal of the american society of nephrology
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 4.451
H-Index - 279
eISSN - 1533-3450
pISSN - 1046-6673
DOI - 10.1681/asn.2010040377
Subject(s) - epithelial sodium channel , aldosterone , purinergic receptor , medicine , endocrinology , nephron , excretion , chemistry , sodium , receptor , biology , kidney , organic chemistry
The mechanisms underlying "aldosterone escape," which refers to the excretion of sodium (Na(+)) during high Na(+) intake despite inappropriately increased levels of mineralocorticoids, are incompletely understood. Because local purinergic tone in the aldosterone-sensitive distal nephron downregulates epithelial Na(+) channel (ENaC) activity, we tested whether this mechanism mediates aldosterone escape. Here, urinary ATP concentration increased with dietary Na(+) intake in mice. Physiologic concentrations of ATP decreased ENaC activity in a dosage-dependent manner. P2Y(2)(-/-) mice, which lack the purinergic receptor, had significantly less increased Na(+) excretion than wild-type mice in response to high-Na(+) intake. Exogenous deoxycorticosterone acetate and deletion of the P2Y(2) receptor each modestly increased the resistance of ENaC to changes in Na(+) intake; together, they markedly increased resistance. Under the latter condition, ENaC could not respond to changes in Na(+) intake. In contrast, as a result of aldosterone escape, wild-type mice had increased Na(+) excretion in response to high-Na(+) intake regardless of the presence of high deoxycorticosterone acetate. These data suggest that control of ENaC by purinergic signaling is necessary for aldosterone escape.