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Inhibition of the purinergic P2X7 receptor improves renal perfusion in angiotensin-II-infused rats

Menzies, RI; Howarth, AR; Unwin, RJ; Tam, FWK; Mullins, JJ; Bailey, MA; (2015) Inhibition of the purinergic P2X7 receptor improves renal perfusion in angiotensin-II-infused rats. Kidney International , 88 (5) pp. 1079-1087. 10.1038/ki.2015.182. Green open access

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Abstract

Chronic activation of the renin angiotensin system promotes hypertension, renal microvascular dysfunction, tissue hypoxia and inflammation. We found previously that the injurious response to excess angiotensin II (ANGII) is greater in F344 rats, whereas Lewis rats are renoprotected, despite similar hypertension. We further identified p2rx7, encoding the P2X7 receptor (P2X7R), as a candidate gene for differential susceptibility and here we have tested the hypothesis that activation of P2X7R promotes vascular dysfunction under high ANGII tone. 14-day infusion of ANGII at 30ng/min into F344 rats increased blood pressure by ~15mmHg without inducing fibrosis or albuminuria. In vivo pressure natriuresis was suppressed, medullary perfusion reduced by ~50% and the cortico-medullary oxygenation gradient disrupted. Selective P2X7R antagonism restored pressure natriuresis, promoting a significant leftward shift in the intercept and increasing the slope. Sodium excretion was increased 6 fold and blood pressure normalized. The specific P2X7R antagonist AZ11657312 increased renal medullary perfusion, but only in ANGII-treated rats. Tissue oxygenation was improved by P2X7R blockade, particularly in poorly oxygenated regions of the kidney. Activation of P2X7R induces microvascular dysfunction and regional hypoxia when ANGII is elevated. These pro-inflammatory effects may contribute to progression of renal injury induced by chronic ANGII.

Type: Article
Title: Inhibition of the purinergic P2X7 receptor improves renal perfusion in angiotensin-II-infused rats
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/ki.2015.182
Publisher version: https://doi.org/10.1038/ki.2015.182
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: ATP; blood oxygenation level-dependent magnetic resonance imaging; kidney disease; kidney injury; purinergic
UCL classification: UCL
UCL > Provost and Vice Provost Offices
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/1468581
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