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

FASEB J. 2010 Jun;24(6):2056-65. doi: 10.1096/fj.09-151506. Epub 2010 Jan 22.


Apical release of ATP and UTP can activate P2Y(2) 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 P2Y(2) receptors in mice (P2Y(2)(-/-); littermates to wild-type mice) or inhibition of apical P2Y-receptor 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, P2Y(2)(-/-) 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 P2Y(2)(-/-) mice. The studies indicate a key role of the apical ATP/UTP-P2Y(2)-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / urine
  • Aldosterone / pharmacology
  • Animals
  • Blood Pressure / drug effects
  • Cells, Cultured
  • Electrophysiology
  • Epithelial Sodium Channels / metabolism*
  • Homeostasis / drug effects
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mineralocorticoids / pharmacology
  • Nephrons / cytology
  • Nephrons / drug effects
  • Nephrons / metabolism
  • Patch-Clamp Techniques
  • Receptors, Purinergic P2 / physiology*
  • Receptors, Purinergic P2Y2
  • Signal Transduction
  • Sodium, Dietary / administration & dosage*
  • Sodium, Dietary / pharmacology*
  • Uridine Triphosphate / urine


  • Epithelial Sodium Channels
  • Mineralocorticoids
  • P2ry2 protein, mouse
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2Y2
  • Sodium, Dietary
  • Aldosterone
  • Adenosine Triphosphate
  • Uridine Triphosphate