Purinergic inhibition of ENaC produces aldosterone escape

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.