The renal and blood pressure response to low sodium diet in P2X4 receptor knockout mice

Abstract

In the kidney, purinergic (P2) receptor‐mediated ATP signaling has been shown to be an important local regulator of epithelial sodium transport. Appropriate sodium regulation is crucial for blood pressure (BP) control and disturbances in sodium balance can lead to hypo‐ or hypertension. Links have already been established between P2 receptor signaling and the development of hypertension, attributed mainly to vascular and/or inflammatory effects. A transgenic mouse model with deletion of the P2X4 receptor (P2X4−/−) is known to have hypertension, which is thought to reflect endothelial dysfunction and impaired nitric oxide (NO) release. However, renal function in this model has not been characterized; moreover, studies in vitro have shown that the P2X4 receptor can regulate renal epithelial Na+ channel (ENaC) activity. Therefore, in the present study we investigated renal function and sodium handling in P2X4−/− mice, focusing on ENaC‐mediated Na+ reabsorption. We confirmed an elevated BP in P2X4−/− mice compared with wild‐type mice, but found that ENaC‐mediated Na+ reabsorption is no different from wild‐type and does not contribute to the raised BP observed in the knockout. However, when P2X4−/− mice were placed on a low sodium diet, BP normalized. Plasma aldosterone concentration tended to increase according to sodium restriction status in both genotypes; in contrast to wild‐types, P2X4−/− mice did not show an increase in functional ENaC activity. Thus, although the increased BP in P2X4−/− mice has been attributed to endothelial dysfunction and impaired NO release, there is also a sodium‐sensitive component.

Extracellular Nucleotides and P2 Receptors in Renal Function

“…P2X4 receptor blockade with PSB12054 in ANG II-infused rats increased afferent and efferent arteriole resistance by 78 and 100%, respectively, leading to 51% reduction in single-nephron GFR (154). The elevated blood pressure may reflect endothelial dysfunction (impaired NO release), as has also been found in P2X4 receptor knockout mice (566), although this model also shows salt sensitivity (107), which is probably NO independent (495).…”

“…Nucleotide release from endothelial cells is triggered by laminar flow (542), a mechanosensory stimulus unique to blood vessels, ductal parts of exocrine glands, and the renal tubular system. The endothelial P2 receptor was suggested to be the P2X4 receptor (566), but recent results challenge this finding and provide good evidence for the P2Y 2 receptor (432,542), and both receptors may contribute (107). Endothelial nucleotide release purportedly involves Panx1 and Panx2, and the mechanosensory ion channel Piezo1 has been proposed as the endothelial molecular flow sensor (542).…”

“…Analysis of the human kidney transcriptome found that of tags for 258 genes conferring transport properties, the only P2X receptor detected in significant amounts in the CD was the P2X4 receptor (85). Studies in vitro suggest that P2X4 receptor activation also inhibits ENaC (473,553), and studies in a P2X4 receptor null mouse suggest that this receptor may be important in the modulation of sodium transport by aldosterone (107). On the other hand, activation of basolateral P2X4 receptors has been found to stimulate ENaC activity in Xenopus CCD A6 cells (507).…”

Resolving the Ionotropic P2X4 Receptor Mystery Points towards a New Therapeutic Target for Cardiovascular Diseases

“…However, regulation of ENaC activity by the P2X4R is not linear, and ATP may exert a dual role depending on sodium and body fluid composition. In low-salt conditions, stimulation of the P2X4R increases ENaC activity, while in salt-overload conditions the P2X4R exerts an opposite effect and promotes natriuresis [ 147 , 148 ]. As mentioned before, P2X4R - null mice exhibit a hypertensive phenotype [ 148 ].…”

“…In low-salt conditions, stimulation of the P2X4R increases ENaC activity, while in salt-overload conditions the P2X4R exerts an opposite effect and promotes natriuresis [ 147 , 148 ]. As mentioned before, P2X4R - null mice exhibit a hypertensive phenotype [ 148 ]. Therefore, it is tempting to speculate that in patients with essential hypertension, P2X4R agonists may contribute to promote natriuresis and to lower blood pressure.…”