ENaC, renal sodium excretion and extracellular ATP

Abstract

Sodium balance determines the extracellular fluid volume and sets arterial blood pressure (BP). Chronically raised BP (hypertension) represents a major health risk in Western societies. The relationship between BP and renal sodium excretion (the pressure/natriuresis relationship) represents the key element in defining the BP homeostatic set point. The renin-angiotensin-aldosterone system (RAAS) makes major adjustments to the rates of renal sodium secretion, but this system works slowly over a period of hours to days. More rapid adjustments can be made by the sympathetic nervous system, although the kidney can function well without sympathetic nerves. Attention has now focussed on regulatory mechanisms within the kidney, including extracellular nucleotides and the P2 receptor system. Here, we discuss how extracellular ATP can control renal sodium excretion by altering the activity of epithelial sodium channels (ENaC) present in the apical membrane of principal cells. There remains considerable controversy over the molecular targets for released ATP, although the P2Y(2) receptor has received much attention. We review the available data and reflect on our own findings in which ATP-activated P2Y and P2X receptors make adjustments to ENaC activity and therefore sodium excretion.

Fig. 1

A summary of known effects of P2R activation on ENaC activity taken from experiments using renal principal cells (PCs) or distal nephron-derived cell lines. Relevant references are superscripted. In a, effects where 5 min or less are left between P2R activation and measurements of ENaC activity. All but apical P2X_4/6 activation decrease the activity of ENaC. Apical P2X_4/6 has the ability to inhibit or potentiate ENaC activity depending on the concentration of luminal Na⁺. Noteworthy is that basolaterally expressed P2X₄ receptors have not been reported to affect ENaC activity. In b, effects where 15–30 min are left between P2R activation and measurement of ENaC activity. All apically expressed P2Rs inhibit ENaC, although the ability of P2Y receptors to inhibit ENaC is less than that in a (from 49–56% to 16%). The potentiating effect of apical P2X_4/6 receptors (when luminal Na⁺ is low) has not been investigated over a 30-min period, but a potentiating effect of basolaterally expressed P2X₄-like receptors has been reported