Bradykinin acutely inhibits activity of the epithelial Na+ channel in mammalian aldosterone-sensitive distal nephron

Oleg Zaika, Mykola Mamenko, Roger G. O'Neil, Oleh Pochynyuk

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Activation of the renal kallikrein-kinin system results in natriuresis and diuresis, suggesting its possible role in renal tubular sodium transport regulation. Here, we used patch-clamp electrophysiology to directly assess the effects of bradykinin (BK) on the epithelial Na+ channel (ENaC) activity in freshly isolated split-opened murine aldosterone-sensitive distal nephrons (ASDNs). BK acutely inhibits ENaC activity by reducing channel open probability (Po) in a dose-dependent and reversible manner. Inhibition of B2 receptors with icatibant (HOE-140) abolished BK actions on ENaC. In contrast, activation of B1 receptors with the selective agonist Lys-des-Arg9-BK failed to reproduce BK actions on ENaC. This is consistent with B2 receptors playing a critical role in mediating BK signaling to ENaC. BK has little effect on ENaC Po when Gq/11 was inhibited with Gp antagonist 2A. Moreover, inhibition of phospholipase C (PLC) with U73122, but not saturation of cellular cAMP levels with the membrane-permeable nonhydrolysable cAMP analog 8-cpt-cAMP, prevents BK actions on ENaC activity. This argues that BK stimulates B2 receptors with subsequent activation of Gq/11-PLC signaling cascade to acutely inhibit ENaC activity. Activation of BK signaling acutely depletes apical PI(4,5)P2 levels. However, inhibition of Ca2+ pump SERCA of the endoplasmic reticulum with thapsigargin does not prevent BK signaling to ENaC. Furthermore, caffeine, while producing a similar rise in [Ca2+]i as in response to BK stimulation, fails to recapitulate BK actions on ENaC. Therefore, we concluded that BK acutely inhibits ENaC Po in mammalian ASDN via stimulation of B2 receptors and following depletion of PI(4,5)P2, but not increases in [Ca2+]i.

Original languageEnglish (US)
Pages (from-to)1105-1115
Number of pages11
JournalAmerican Journal of Physiology - Renal Physiology
Volume300
Issue number5
DOIs
StatePublished - May 1 2011
Externally publishedYes

    Fingerprint

Keywords

  • Cortical collecting duct
  • Hypertension
  • Local kinins
  • Sodium reabsorption

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this