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

Menzies, RI; Unwin, RJ; Dash, RK; Beard, DA; Cowley, AW; Carlson, BE; Mullins, JJ; (2013) Effect of P2X4 and P2X7 receptor antagonism on the pressure diuresis relationship in rats. Front Physiol , 4 , Article 305. 10.3389/fphys.2013.00305. Green open access

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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.

Type: Article
Title: Effect of P2X4 and P2X7 receptor antagonism on the pressure diuresis relationship in rats.
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fphys.2013.00305
Publisher version: http://dx.doi.org/10.3389/fphys.2013.00305
Language: English
Additional information: © 2013 Menzies, Unwin, Dash, Beard, Cowley, Carlson, Mullins and Bailey. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. PMCID: PMC3807716
Keywords: ATP, kidney disease, purinergic, renal injury, renal vascular resistance
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1417387
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