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 (Po) 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 Po, 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 P2Y-receptor activation in wild-type mice prevents dietary Na⁺-induced lowering of ENaC Po. Although they lack suppression of ENaC Po 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 Po in the ASDN in response to an increase in Na⁺ intake, thereby contributing to NaCl homeostasis and blood pressure regulation.--Pochynyuk, O., Rieg, T., Bugaj, V., Schroth, J., Fridman, A., Boss, G. R., Insel, P. A., Stockand, J. D., Vallon, V. Dietary Na⁺ inhibits the open probability of the epithelial sodium channel in the kidney by enhancing apical P2Y₂-receptor tone.