TY - JOUR
T1 - Diminished paracrine regulation of the epithelial Na+ channel by purinergic signaling in mice lacking connexin 30
AU - Mironova, Elena
AU - Peti-Peterdi, Janos
AU - Bugaj, Vladislav
AU - Stockand, James D.
PY - 2011/1/14
Y1 - 2011/1/14
N2 - 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 wildtype 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.
AB - 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 wildtype 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.
UR - http://www.scopus.com/inward/record.url?scp=78651383191&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78651383191&partnerID=8YFLogxK
U2 - 10.1074/jbc.M110.176552
DO - 10.1074/jbc.M110.176552
M3 - Article
C2 - 21075848
AN - SCOPUS:78651383191
SN - 0021-9258
VL - 286
SP - 1054
EP - 1060
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 2
ER -