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 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.
Pochynyuk
Oleh
O
Department of Physiology, University of Texas Health Science Center, San Antonio, Texas, USA.
Rieg
Timo
T
Bugaj
Vladislav
V
Schroth
Jana
J
Fridman
Alla
A
Boss
Gerry R
GR
Insel
Paul A
PA
Stockand
James D
JD
Vallon
Volker
V
D000255:Adenosine Triphosphate / Q000652:urine; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D004594:Electrophysiology; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008901:Mineralocorticoids / Q000494:pharmacology; D009399:Nephrons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058473:Receptors, Purinergic P2Y2; D015398:Signal Transduction; D012982:Sodium, Dietary / Q000008:administration & dosage* / Q000494:pharmacology*; D014544:Uridine Triphosphate / Q000652:urine
D053503:Epithelial Sodium Channels; D008901:Mineralocorticoids; C546386:P2ry2 protein, mouse; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D012982:Sodium, Dietary; D000450:Aldosterone; D000255:Adenosine Triphosphate; D014544:Uridine Triphosphate