Dietary Na⁺inhibits the open probability of the epithelial sodium channel in the kidney by enhancing apical P2Y₂‐receptor tone

Abstract

Apical release of ATP and UTP can activate P2Y(2) receptors in the aldosterone-sensitive distal nephron (ASDN) and inhibit the open probability (P(o)) of the epithelial sodium channel (ENaC). Little is known, however, about the regulation and physiological relevance of this system. Patch-clamp studies in freshly isolated ASDN provide evidence that increased dietary Na(+) intake in wild-type mice lowers ENaC P(o), consistent with a contribution to Na(+) homeostasis, and is associated with increased urinary concentrations of UTP and the ATP hydrolytic product, ADP. Genetic deletion of P2Y(2) receptors in mice (P2Y(2)(-/-); littermates to wild-type mice) or inhibition of apical P2Y-receptor activation in wild-type mice prevents dietary Na(+)-induced lowering of ENaC P(o). Although they lack suppression of ENaC P(o) by dietary NaCl, P2Y(2)(-/-) mice do not exhibit NaCl-sensitive blood pressure, perhaps as a consequence of compensatory down-regulation of aldosterone levels. Consistent with this hypothesis, clamping mineralocorticoid activity at high levels unmasks greater ENaC activity and NaCl sensitivity of blood pressure in P2Y(2)(-/-) mice. The studies indicate a key role of the apical ATP/UTP-P2Y(2)-receptor system in the inhibition of ENaC P(o) in the ASDN in response to an increase in Na(+) intake, thereby contributing to NaCl homeostasis and blood pressure regulation.

Purinergic signalling in the kidney in health and disease

“…Resting ENaC activity was greater in P2Y 2 −/− receptor mice than controls suggesting that local ATP may be involved in the regulation of basal ENaC activity in the murine collecting duct [289,290]. Additional studies from the same laboratory demonstrated that ENaC downregulation in response to sodium restriction was lost in the P2Y 2 null mice, suggesting a role for the receptor in the renal response to altered sodium intake [291]. Despite this, the hypertension was not saltsensitive, suggesting that these renal changes are compensated for elsewhere.…”

Angiotensin II Increases Activity of the Epithelial Na+ Channel (ENaC) in Distal Nephron Additively to Aldosterone

“…Animals were maintained on standard rodent regimen (PURINA 5001) and had free access to tap water. For some experiments, mice were injected with deoxycorticosterone acetate (DOCA) for 3 consecutive days (2.4 mg/injection per animal) prior to the experimentation as we have done previously (29).…”

“…Tissue Isolation-The procedure for isolation of the ASDNs containing the connecting tubule and the CCD suitable for electrophysiology and Ca 2ϩ -imaging has been described previously (27)(28)(29). Briefly, mice were sacrificed by CO 2 administration followed by cervical dislocation; the kidneys were removed immediately.…”

The touching story of purinergic signaling in epithelial and endothelial cells

“…1 Nucleotide metabolism in a nutshell. UTP is identically released and degraded and has been found in both gastrointestinal [32], respiratory [33][34][35][36], and renal epithelium [37][38][39]. Since the P2Y2 receptor has equal affinity for both ATP and UTP, both these mediators can activate the receptor.…”

“…The most studied mechanism of ENaC activity involves membrane trafficking of the protein [42], but a recent study of the P2Y2 receptor-mediated inhibitory response suggests that purinergic control is conveyed by changes in channel open probability rather than plasma membrane levels of the protein [39]. The way that P2Y2 receptor activation influences ENaC activity has previously been attributed to PLC activation and PIP2 depletion [43].…”