Flow‐sensitive K+‐coupled ATP secretion modulates ENaC activity in the distal nephron

Abstract

The epithelial Na+ channel (ENaC) in the aldosterone‐sensitive distal nephron (ASDN) is under tonic inhibition by paracrine purinergic signaling responding to changes in dietary sodium intake. Normal BK(Ca) channel function is required for ATP secretion in the ASDN. We test here whether ATP secreted through connexin channels in a coupled manner with K+ efflux through BK(Ca) channels is required for inhibitory purinergic regulation of ENaC in response to increases in sodium intake. Inhibition of connexin relieves purinergic inhibition of ENaC. Deletion of the BK‐β4 regulatory subunit, which is required for normal channel function and ATP secretion, mutes sodium intake‐dependent increases in urinary ATP resulting in inappropriately elevated ENaC activity. ENaC in BK‐β4 null mice, though, responds normally to exogenous ATP consistent with lower urinary ATP causing elevated activity. Moreover, disruption of purinergic regulation increases ENaC activity in wild type but not null mice. Consequently, sodium excretion is impaired in null mice. These results demonstrate that ATP secreted into the ASDN in a BK(Ca) channel‐dependent manner is physiologically available for inhibition of ENaC in response to changes in sodium intake. Impaired sodium excretion resulting form the loss of normal inhibitory purinergic control of ENaC likely contributes to the elevated blood pressure of BK‐β4 null mice.