Effect of P2X4 and P2X7 receptor antagonism on the pressure diuresis relationship in rats

Abstract

Reduced glomerular filtration, hypertension and renal microvascular injury are hallmarks of chronic kidney disease, which has a global prevalence of ~10%. We have shown previously that the Fischer (F344) rat has lower GFR than the Lewis rat, and is more susceptible to renal injury induced by hypertension. In the early stages this injury is limited to the pre-glomerular vasculature. We hypothesized that poor renal hemodynamic function and vulnerability to vascular injury are causally linked and genetically determined. In the present study, normotensive F344 rats had a blunted pressure diuresis relationship, compared with Lewis rats. A kidney microarray was then interrogated using the Endeavour enrichment tool to rank candidate genes for impaired blood pressure control. Two novel candidate genes, P2rx7 and P2rx4, were identified, having a 7− and 3− fold increased expression in F344 rats. Immunohistochemistry localized P2X4 and P2X7 receptor expression to the endothelium of the pre-glomerular vasculature. Expression of both receptors was also found in the renal tubule; however there was no difference in expression profile between strains. Brilliant Blue G (BBG), a relatively selective P2X7 antagonist suitable for use in vivo, was administered to both rat strains. In Lewis rats, BBG had no effect on blood pressure, but increased renal vascular resistance, consistent with inhibition of some basal vasodilatory tone. In F344 rats BBG caused a significant reduction in blood pressure and a decrease in renal vascular resistance, suggesting that P2X7 receptor activation may enhance vasoconstrictor tone in this rat strain. BBG also reduced the pressure diuresis threshold in F344 rats, but did not alter its slope. These preliminary findings suggest a physiological and potential pathophysiological role for P2X7 in controlling renal and/or systemic vascular function, which could in turn affect susceptibility to hypertension-related kidney damage.

Purinergic signalling in the kidney in health and disease

“…This reflects P2Y-mediated production of NO [86]. More recent data have shown vasoactive actions of P2X4 and/or P2X7 in the rat renal artery [242]. It would appear that P2 receptor 'tone' influences renal vascular resistance, with P2Y-mediated vasodilatation opposing P2X-mediated vasoconstriction.…”

“…In the smooth muscle of the larger renal arteries, P2X2 receptor subunits have been immunolocalised [146,375], and at a molecular level, P2X4 receptor subunits are found, at least in arcuate and interlobular arteries [127]. At a protein level, however, P2X4 expression is limited to the vascular endothelium [242]. P2X7 receptors are also expressed in the healthy kidney: expression in the vascular smooth muscle and outeradventitium is very low [218], whereas functionally significant expression is observed in the endothelium [242].…”

“…At a protein level, however, P2X4 expression is limited to the vascular endothelium [242]. P2X7 receptors are also expressed in the healthy kidney: expression in the vascular smooth muscle and outeradventitium is very low [218], whereas functionally significant expression is observed in the endothelium [242]. Of the P2Y receptors, P2Y 1 is expressed in the endothelium of the large arteries and both afferent and efferent arterioles [375].…”

The Dark Side of Extracellular ATP in Kidney Diseases

“…63 In vivo inhibition of P2X 1 R with PPADS or IP5I inhibits autoregulatory control of wholekidney blood flow, 64 whereas the infusion of Brilliant Blue G, a P2X 7 R antagonist, to Fischer rats and Dahl salt-sensitive rats reduced arterial BP and decreased renal vascular resistance. 65,66 On the other hand, P2Y 2 R modulates, via paracrine signaling, renal sodium excretion in the distal nephron in mice, thus playing a pivotal role in maintaining arterial BP within a normal range. 67 In conclusion, although it is difficult to anticipate the net effect of modulating eATP signaling on arterial BP, a reduction in vasoconstriction tone and in renal salt and water homeostasis suggests a potential benefit in hypertension.…”

Brilliant Blue Dyes in Daily Food: How Could Purinergic System Be Affected?

“…Both parameters were diminished in F344 rats (possibly due to an increase in the vasoconstrictor tone). In addition, BBG suppressed the diuresis pressure threshold in F344 rats [78]. …”