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) |
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Pages (from-to) | 2056-2065 |
Number of pages | 10 |
Journal | FASEB Journal |
Volume | 24 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2010 |
Keywords
- ATP
- Aldosterone
- Blood pressure
- Distal nephron
- Nucleotide receptors
ASJC Scopus subject areas
- Genetics
- Molecular Biology
- Biochemistry
- Biotechnology