Intrinsic control of sodium excretion in the distal nephron by inhibitory purinergic regulation of the epithelial Na(+) channel

Abstract

Purpose of review: This review summarizes the new evidence for an intrinsic control system in the aldosterone-sensitive distal nephron in which purinergic signaling regulates sodium transport and governs renal sodium excretion.

Recent findings: Electrophysiological studies identify epithelial Na(+) channels (ENaC) as final effectors of purinergic signaling via P2Y(2) receptors in the distal nephron. Inhibition of ENaC by autocrine/paracrine purinergic signaling reduces sodium reabsorption allowing an appropriately graded pressure-natriuresis response when delivery of sodium to the distal nephron is high. Disruption of this intrinsic control mechanism decreases sodium excretion and therefore has a prohypertensive effect. Because purinergic inhibition of ENaC is tonic yet submaximal, its enhancement increases sodium excretion and therefore has an antihypertensive action.

Summary: Purinergic inhibitory regulation of ENaC is a key component of an intrinsic control system that enables the distal nephron to respond appropriately to the delivered load of sodium. This control system is physiologically important and functions in parallel with extrinsic control by the renin-angiotensin-aldosterone system, enabling sodium excretion to keep pace with sodium intake, especially when intake is high, and thereby maintaining arterial blood pressure. Disruption of intrinsic control of sodium transport by the distal nephron likely contributes to diseases such as arterial hypertension.

Figure 1. Inhibitory purinergic regulation of ENaC mediates intrinsic control of sodium transport in the ASDN

A. A schematic of the ASDN showing the components mediating intrinsic control. B. A single channel, cell-attached patch clamp experiment on a principal cell in the isolated, split-open ASDN showing the effects of ATP on ENaC in the apical membrane. In this experiment, inward current is downwards and the closed state is noted with C. Areas below the gray bars, 1 and 2, are shown below on a faster time scale. Data originally presented in [10]. C. Summary of these effects of ATP on ENaC open probability in isolated, split open ASDN. Experiments were similar to that shown in 1B. Data originally presented in [8]. *significant decrease vs. before treatment. D. Dose response curves showing the effects of ATP and UTP on ENaC activity in isolated, split-open ASDN. Experiments similar to that shown in 1B. Data originally presented in [10].

Figure 2. There is purinergic tone in the ASDN

A. A single channel, cell-attached patch clamp experiment showing the effects of hexokinase on ENaC activity in an ASDN naïve to exogenous ATP. In this experiment, inward current is downwards. Areas below the bars, 1 and 2, are shown below on a faster time scale. B. Summary showing the effects of hexokinase on ENaC activity in patch clamp experiments similar to that in 2A. *significant increase vs. before treatment with hexokinase. Data originally presented in [8].

Figure 3. Purinergic inhibition of ENaC allows this channel to respond appropriately to sodium balance

Single channel current traces of ENaC in cell attached patches on ASDN isolated from mice maintained on a sodium free (A) and a high sodium diet (B) without (top) and with (bottom) addition of suramin plus hexokinase to the bathing solution. Inward current is downward with closed state noted with C. *significant decrease compared to sodium free (<0.01%) condition; **significant increase compared to control. Data originally presented in [9]. C. Summary graph showing the effects on ENaC activity of suramin plus hexokinase (gray bars) as compared to basal activity (black bars) in ASDN from mice fed a sodium free, regular sodium and high sodium diet. *significant increase compared to wild-type under identical feeding conditions. Data originally presented in [9]. D. Summary graph comparing ENaC activity in ASDN from wild-type (black bars) versus P2Y₂ receptor knockout (gray bars) mice maintained with sodium free, regular sodium and high sodium diets. Data originally presented in [9]. E. Summary graph showing fractional ENaC activity (activity with high sodium feeding / activity with sodium free feeding) in wild-type (wt) and P2Y₂ receptor and Cx30 knockout mice in the absence (gray circles) and presence (black circles) supplementing with DOCA. Activity calculated as fNP_o where f is the frequency of observing at least one active ENaC in a patch, N is the mean number of ENaC per patch that contained active channels, and P_o is open probability. Data originally presented in [10] and [22].

Figure 4. Intrinsic control of ENaC by inhibitory purinergic signaling facilitates sodium excrtion

Cellular model showing the protein players and signals modulating intrinsic control of ENaC in the ASDN.