Purinergic Inhibition of ENaC Produces Aldosterone Escape

Abstract

The mechanisms underlying "aldosterone escape," which refers to the excretion of sodium (Na ϩ ) during high Na ϩ intake despite inappropriately increased levels of mineralocorticoids, are incompletely understood. Because local purinergic tone in the aldosterone-sensitive distal nephron downregulates epithelial Na ϩ channel (ENaC) activity, we tested whether this mechanism mediates aldosterone escape. Here, urinary ATP concentration increased with dietary Na ϩ intake in mice. Physiologic concentrations of ATP decreased ENaC activity in a dosage-dependent manner. P2Y 2 Ϫ/Ϫ mice, which lack the purinergic receptor, had significantly less increased Na ϩ excretion than wild-type mice in response to high-Na ϩ intake. Exogenous deoxycorticosterone acetate and deletion of the P2Y 2 receptor each modestly increased the resistance of ENaC to changes in Na ϩ intake; together, they markedly increased resistance. Under the latter condition, ENaC could not respond to changes in Na ϩ intake. In contrast, as a result of aldosterone escape, wild-type mice had increased Na ϩ excretion in response to high-Na ϩ intake regardless of the presence of high deoxycorticosterone acetate. These data suggest that control of ENaC by purinergic signaling is necessary for aldosterone escape.

Purinergic signalling in the kidney in health and disease

“…'Aldosterone escape' refers to the excretion of sodium during high sodium intake; local purinergic tone in the aldosterone-sensitive distal nephron downregulates ENaC activity. P2Y 2 −/− mice had significantly less increased sodium excretion than wild-type mice [354]. It was concluded that control of ENaC by purinergic signalling is necessary for aldosterone escape and this was supported by another laboratory in a later paper, and in addition, it identified a potential role for NO and prostaglandins in response to aldosterone [434].…”

Impaired natriuretic response to high-NaCl diet plus aldosterone infusion in mice overexpressing human CD39, an ectonucleotidase (NTPDase1)

“…ENaC could also be considered a candidate mediator of escape (26). Although protein levels have been shown to be inconsistently regulated in this model across studies, it is possible that the activity of the whole channel is regulated in another fashion, perhaps by proteolytic cleavage or trafficking.…”

“…In summary, our data support the concept that extracellular nucleotides facilitate natriuresis; they also reveal an aldosterone-independent downregulation of major renal sodium transporters and channel subunits by purinergic signaling. purinergic receptors; extracellular nucleotides; ectonucleotidases; nucleoside triphosphate diphosphohydrolase-1; aldosterone; sodium transporters EXTRACELLULAR NUCLEOTIDES (ATP/ADP/UTP), acting through type-2 purinergic receptors (P2), potentially regulate renal tubular transport of water and sodium, and thereby urinary concentrating ability (5,7,11,18,19,23,25,26,28,29,33,39). P2 receptor signal modulation is controlled by a narrow range of extracellular concentrations of ATP and related nucleotides, which are mediated through regulated release from cells and rapidly hydrolyzed by ectonucleotidases (10).…”

Intrarenal localization of the plasma membrane ATP channel pannexin1

“…The recent discoveries that Panx1 channels serve as K ϩ sensors for changes in the extracellular milieu (29,34,39) may help establish further links between renal tubular K ϩ , ATP, and purinergic signaling (11). Therefore, via ATP release and purinergic inhibition of renal epithelial salt and water transport, Panx1 may participate in important renal physiological mechanisms such as high-K ϩ diet-induced elevations in tubular flow, the aldosterone paradox, and aldosterone escape (11,38).…”