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.

Purinergic signalling in the kidney in health and disease

“…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 P2X4/6 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 (reproduced from [414], with permission from Springer) sensitive distal nephron [309]. 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].…”

Extracellular GTP is a Potent Water-Transport Regulator via Aquaporin 5 Plasma-Membrane Insertion in M1-CCD Epithelial Cortical Collecting Duct Cells

“…More recently, it has been suggested that ATP is released as a co-transmitter from sympathetic nerve varicosities, and that it can bind the basolateral P2 purinoceptors and influence sodium and water transport [37,38]. However, one of the major issues in understanding purinergic signaling continues to be the limited consensus for the nucleotide release phenomenon.…”

The Polarized Effect of Intracellular Calcium on the Renal Epithelial Sodium Channel Occurs as a Result of Subcellular Calcium Signaling Domains Maintained by Mitochondria

“…2, B and C (the same experiment repeated in the absence of mitochondrial calcium uptake) are the same, suggesting that the polarized effect of [Ca 2ϩ ] i on ENaC is dependent on mitochondrial calcium uptake. ATP has been shown repeatedly to inhibit ENaC when applied apically (a process that is dependent on an increase in [Ca 2ϩ ] i (24)). Fig.…”