Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 2, Pages 1054-1060Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.176552
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Funding
- National Institutes of Health [R01DK59594]
- American Heart Association (AHA) [0640054N, 0640056N]
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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 wildtype 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.
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