Diminished Paracrine Regulation of the Epithelial Na+ Channel by Purinergic Signaling in Mice Lacking Connexin 30

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 Blood pressure is under negative feedback control. A key factor setting blood pressure is systemic sodium balance. Under normal conditions, as sodium intake increases renal sodium excretion increases to maintain sodium balance and thus, blood pressure. The renin-angiotensin-aldosterone system (RAAS) 2 plays a central role in negative feedback regulation of blood pressure. This system responds to changes in blood pressure and effective circulating volume: both of which are tied to systemic sodium levels. A key end-effector of RAAS, specifically the mineralocorticoid, aldosterone, is the epithelial Na ϩ channel (ENaC) localized to the apical membrane of principal cells in the aldosterone-sensitive distal nephron (ASDN; (1-3). Plasma sodium levels are fine-tuned in the ASDN through discretionary sodium reabsorption mediated chiefly by the activity of ENaC. Thus, ENaC activity and regulation of this channel are critical to control of blood pressure. This is best appreciated by considering that gain and loss of ENaC function increase and decrease, respectively, blood pressure by impacting renal sodium excretion (4 -7).Emerging evidence supports that local control of ENaC by autocrine/paracrine regulation also plays an important role in setting channel activity in response to changing sodium intake (8 -12). For instance, local control by a purinergic system intrinsic to the ASDN modulates the open probability of ENaC and thus, sodium excretion, in response to changes in sodium intake (8, 9, 13). There are two types of purinergic (P2) receptors: classic seven-transmembrane G protein-coupled receptors, metabotropic P2Y receptors; and ionotropic P2X receptors, which function as ligand-gated non-selective ion channels (14 -16). The P2Y 2 receptor important for control of ENaC is in the apical plasma membrane of principal cells and coupled to PLC via G q/11 (13, 16 -18).Mice lacking the P2Y 2 receptor have impaired sodium excretion and increases in blood pressure associated with decreased plasma renin and aldosterone, as well as potassium (8). Gain of ENaC function similarly leads to hypertension associated with decreased plasma renin, aldosterone, and potassium levels (4 -7). Plasma potassium levels are decreased, in part, because K ϩ secretion increases in the ASDN as Na ϩ is reabsorbed here via ENaC. Plasma renin and aldosterone levels decrease as part of a feedback response attempting to mitigate inappropriate sodium retention. In the P2Y 2 knock-out mouse, ENaC is hyperactive, having increased open probability, and unable to respond normally to changes in sodium intake due to disruptio...

Purinergic signalling in the kidney in health and disease

“…It was claimed that gap junction Cx37 and Cx40 transduce purinergic signals mediating renal autoregulation [364]. In a recent paper, it was shown that ATP release through Cx30 is part of a local regulatory system intrinsic to the aldosterone-sensitive distal nephron important for control of sodium excretion [246]. They showed that loss of paracrine ATP feedback regulation of ENaC to respond to changes in sodium levels contributed to salt-sensitive hypertension in Cx30 −/− mice.…”

Vesicular and conductive mechanisms of nucleotide release

“…In another study, increasing Na + intake resulted in enhanced urinary ATP secretion, which was robust in WT mice but modest in Cx30 −/− animals. Conversely, epithelial Na + channel (ENaC) activity was greater in Cx30-deffcient animals, likely reflecting decreased ATP release-promoted P2Y 2 receptor-evoked ENaC inhibition [130].…”

Renal β-intercalated cells maintain body fluid and electrolyte balance

“…Indeed, the distal nephron is challenged daily by variations in tubular fluid NaCl concentration as a direct consequence of dietary salt intake. Urinary ATP levels have been shown to increase with dietary Na + intake (56,57). We propose a paradigm in which β-ICs would sense the increase in NaCl delivery to the distal nephron and in turn release ATP/PGE 2 to decrease Na + absorption by adjacent PCs.…”