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.
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