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.
Highlights
The epithelial Naϩ channel (ENaC) localized to the apical membrane of principal cells in the aldosterone-sensitive distal nephron
Connexin 30 Is Necessary for Salt-sensitive ATP Release into the Urine—To test if Cx30 has a role in ATP release, in response to increases in sodium intake, we quantified the concentration of ATP in urine
The major finding of this study is that Cx30 is necessary for salt-sensitive regulation of renal sodium excretion as mediated by local purinergic control of ENaC in the aldosterone-sensitive distal nephron (ASDN)
Summary
The epithelial Naϩ channel (ENaC) localized to the apical membrane of principal cells in the aldosterone-sensitive distal nephron Mice lacking the P2Y2 receptor have impaired sodium excretion and increases in blood pressure associated with decreased plasma renin and aldosterone, as well as potassium [8]. Genetic deletion of Cx30 markedly reduces flow-induced ATP release and impairs sodium excretion associated with a pressure natriuresis response, as well as, causes salt-sensitive increases in blood pressure that are countered by benzamil, which is an inhibitor of ENaC [12]. These findings suggest that local ATP released through Cx30 is involved in control of ENaC in the ASDN and that loss of this paracrine control compromises sodium excretion and responses to changes in systemic sodium levels
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