Diminished paracrine regulation of the epithelial Na+ channel by purinergic signaling in mice lacking connexin 30

J Biol Chem. 2011 Jan 14;286(2):1054-60. doi: 10.1074/jbc.M110.176552. Epub 2010 Nov 12.

Abstract

We tested whether ATP release through Connexin 30 (Cx30) is part of a local purinergic regulatory system intrinsic to the aldosterone-sensitive distal nephron (ASDN) important for proper control of sodium excretion; if changes in sodium intake influence ATP release via Cx30; and if this allows a normal ENaC response to changes in systemic sodium levels. In addition, we define the consequences of disrupting ATP regulation of ENaC in Cx30(-/-) mice. Urinary ATP levels in wild-type mice increase with sodium intake, being lower and less dependent on sodium intake in Cx30(-/-) mice. Loss of inhibitory ATP regulation causes ENaC activity to be greater in Cx30(-/-) versus wild-type mice, particularly with high sodium intake. This results from compromised ATP release rather than end-organ resistance: ENaC in Cx30(-/-) mice responds to exogenous ATP. Thus, loss of paracrine ATP feedback regulation of ENaC in Cx30(-/-) mice disrupts normal responses to changes in sodium intake. Consequently, ENaC is hyperactive in Cx30(-/-) mice lowering sodium excretion particularly during increases in sodium intake. Clamping mineralocorticoids high in Cx30(-/-) mice fed a high sodium diet causes a marked decline in renal sodium excretion. This is not the case in wild-type mice, which are capable of undergoing aldosterone-escape. This loss of the ability of ENaC to respond to changes in sodium levels contributes to salt-sensitive hypertension in Cx30(-/-) mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / urine
  • Aldosterone / metabolism
  • Animals
  • Connexin 30
  • Connexins / genetics*
  • Connexins / metabolism*
  • Epithelial Sodium Channels / metabolism*
  • Feedback, Physiological / physiology
  • Hypertension, Renal / genetics
  • Hypertension, Renal / metabolism*
  • Kidney Tubules, Collecting / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Paracrine Communication / physiology*
  • Receptors, Purinergic P2Y2 / metabolism
  • Signal Transduction / physiology
  • Sodium Chloride, Dietary / pharmacology
  • Sodium Chloride, Dietary / urine

Substances

  • Connexin 30
  • Connexins
  • Epithelial Sodium Channels
  • Gjb6 protein, mouse
  • Receptors, Purinergic P2Y2
  • Sodium Chloride, Dietary
  • Aldosterone
  • Adenosine Triphosphate