title: Diminished paracrine regulation of the epithelial Na+ channel by purinergic signaling in mice lacking connexin 30.
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.
authors.affiliation: Department of Physiology, University of Texas Health Science Center, San Antonia, Texas 78229-3900, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Mironova
authors.forename: Janos
authors.initials: J
authors.lastname: Peti-Peterdi
authors.forename: Vladislav
authors.initials: V
authors.lastname: Bugaj
authors.forename: James D
authors.initials: JD
authors.lastname: Stockand
mesh_terms: D000255:Adenosine Triphosphate / Q000652:urine; D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D000075302:Connexin 30; D017630:Connexins / Q000235:genetics* / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D006977:Hypertension, Renal / Q000235:genetics / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019899:Paracrine Communication / Q000502:physiology*; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D017673:Sodium Chloride, Dietary / Q000494:pharmacology / Q000652:urine
chemical_list: D000075302:Connexin 30; D017630:Connexins; D053503:Epithelial Sodium Channels; C100629:Gjb6 protein, mouse; D058473:Receptors, Purinergic P2Y2; D017673:Sodium Chloride, Dietary; D000450:Aldosterone; D000255:Adenosine Triphosphate