Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2056-2065 |
| Number of pages | 10 |
| Journal | FASEB Journal |
| Volume | 24 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2010 |
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Keywords
- Aldosterone
- ATP
- Blood pressure
- Distal nephron
- Nucleotide receptors
ASJC Scopus subject areas
- Biochemistry
- Biotechnology
- Genetics
- Molecular Biology
Cite this
Dietary Na+ inhibits the open probability of the epithelial sodium channel in the kidney by enhancing apical P2Y2-receptor tone. / Pochynyuk, Oleh; Rieg, Timo; Bugaj, Vladislav; Schroth, Jana; Fridman, Alla; Boss, Gerry R.; Insel, Paul A.; Stockand, James D; Vallon, Volker.
In: FASEB Journal, Vol. 24, No. 6, 06.2010, p. 2056-2065.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dietary Na+ inhibits the open probability of the epithelial sodium channel in the kidney by enhancing apical P2Y2-receptor tone
AU - Pochynyuk, Oleh
AU - Rieg, Timo
AU - Bugaj, Vladislav
AU - Schroth, Jana
AU - Fridman, Alla
AU - Boss, Gerry R.
AU - Insel, Paul A.
AU - Stockand, James D
AU - Vallon, Volker
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
KW - Aldosterone
KW - ATP
KW - Blood pressure
KW - Distal nephron
KW - Nucleotide receptors
UR - http://www.scopus.com/inward/record.url?scp=77953519914&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953519914&partnerID=8YFLogxK
U2 - 10.1096/fj.09-151506
DO - 10.1096/fj.09-151506
M3 - Article
C2 - 20097874
AN - SCOPUS:77953519914
VL - 24
SP - 2056
EP - 2065
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 6
ER -