title: Inhibition of the purinergic P2X7 receptor improves renal perfusion in angiotensin-II-infused rats.
abstract: Chronic activation of the renin-angiotensin system promotes hypertension, renal microvascular dysfunction, tissue hypoxia, and inflammation. Despite similar hypertension, an injurious response to excess angiotensin II is greater in F344 than in Lewis rats; the latter displaying renoprotection. Here we studied whether p2rx7, encoding the P2X7 receptor (P2X7R), is a candidate gene for the differential susceptibility to vascular dysfunction under high angiotensin II tone. A 14-day infusion of angiotensin II into F344 rats increased blood pressure by about 15 mm Hg without inducing fibrosis or albuminuria. In vivo pressure natriuresis was suppressed, medullary perfusion reduced by half, and the corticomedullary 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 sixfold and blood pressure normalized. The specific P2X7R antagonist AZ11657312 increased renal medullary perfusion, but only in angiotensin II-treated rats. Tissue oxygenation was improved by P2X7R blockade, particularly in poorly oxygenated regions of the kidney. Thus, activation of P2X7R induces microvascular dysfunction and regional hypoxia when angiotensin II is elevated and these effects may contribute to progression of renal injury induced by chronic angiotensin II.
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK.|Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Menzies
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK.
authors.forename: Amelia R
authors.initials: AR
authors.lastname: Howarth
authors.affiliation: Cardiovascular and Metabolic Diseases (iMed CVMD) R&D, AstraZeneca, Mölndal, Sweden.|UCL Centre for Nephrology, University College London, London, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Unwin
authors.affiliation: Imperial College Renal and Transplant Centre, Department of Medicine, Imperial College London, London, UK.
authors.forename: Frederick W K
authors.initials: FW
authors.lastname: Tam
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bailey
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007672:Kidney Cortex / Q000098:blood supply* / Q000502:physiology; D007679:Kidney Medulla / Q000098:blood supply* / Q000502:physiology; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D012079:Renal Circulation / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D012333:RNA, Messenger; D058486:Receptors, Purinergic P2X7; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D010100:Oxygen