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.
Stockand
James D
JD
Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA. stockand@uthscsa.edu
Mironova
Elena
E
Bugaj
Vladislav
V
Rieg
Timo
T
Insel
Paul A
PA
Vallon
Volker
V
Peti-Peterdi
Janos
J
Pochynyuk
Oleh
O
D000255:Adenosine Triphosphate / Q000652:urine; D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009399:Nephrons / Q000187:drug effects / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012964:Sodium / Q000652:urine; D012982:Sodium, Dietary / Q000494:pharmacology
D053503:Epithelial Sodium Channels; D058473:Receptors, Purinergic P2Y2; D012982:Sodium, Dietary; D003900:Desoxycorticosterone; D000450:Aldosterone; D000255:Adenosine Triphosphate; D012964:Sodium
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