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

Oleh Pochynyuk, Timo Rieg, Vladislav Bugaj, Jana Schroth, Alla Fridman, Gerry R. Boss, Paul A. Insel, James D. Stockand, Volker Vallon

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

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 languageEnglish (US)
Pages (from-to)2056-2065
Number of pages10
JournalFASEB Journal
Volume24
Issue number6
DOIs
StatePublished - Jun 2010

Keywords

  • ATP
  • Aldosterone
  • Blood pressure
  • Distal nephron
  • Nucleotide receptors

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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