Dietary Na+ inhibits the open probability of the epithelial sodium channel in the kidney by enhancing apical P2Y2-receptor tone.

Apical release of ATP and UTP can activate P2Y₂ receptors in the aldosterone-sensitive distal nephron (ASDN) and inhibit the open probability (P_o) of the epithelial sodium channel (ENaC). Little is known, however, about the regulation and physiological relevance of this system. Patch-clamp studies in freshly isolated ASDN provide evidence that increased dietary Na⁺ intake in wild-type mice lowers ENaC P_o, consistent with a contribution to Na⁺ homeostasis, and is associated with increased urinary concentrations of UTP and the ATP hydrolytic product, ADP. Genetic deletion of P2Y₂ receptors in mice (P2Y₂ ^-/-; littermates to wild-type mice) or inhibition of apical P2Yreceptor activation in wild-type mice prevents dietary Na⁺-induced lowering of ENaC P_o. Although they lack suppression of ENaC P_o by dietary NaCl, P2Y₂ ^-/- mice do not exhibit NaCl-sensitive blood pressure, perhaps as a consequence of compensatory down-regulation of aldosterone levels. Consistent with this hypothesis, clamping mineralocorticoid activity at high levels unmasks greater ENaC activity and NaCl sensitivity of blood pressure in P2Y₂^-/- mice. The studies indicate a key role of the apical ATP/UTP-P2Y₂-receptor system in the inhibition of ENaC P_o in the ASDN in response to an increase in Na⁺ intake, thereby contributing to NaCl homeostasis and blood pressure regulation. [ABSTRACT FROM AUTHOR]