title: P2X7 receptor inhibition protects against ischemic acute kidney injury in mice.
abstract: Activation of the purinergic P2X7 receptor (P2X7R) has been associated with the development of experimental nephritis and diabetic and hypertensive nephropathy. However, its role in acute kidney injury (AKI) remains unknown. In this study, we examined the effects of P2X7R inhibition in a murine model of ischemia-reperfusion (I/R)-induced AKI using A438079, a selective inhibitor of P2X7R. At 24 h after I/R, mice developed renal dysfunction and renal tubular damage, which was accompanied by elevated expression of P2X7R. Early administration of A438079 immediately or 6 h after the onset of reperfusion protected against renal dysfunction and attenuated kidney damage whereas delayed administration of A438079 at 24 h after restoration of perfusion had no protective effects. The protective actions of A438079 were associated with inhibition of renal tubule injury and cell death and suppression of renal expression of monocyte chemotactic protein-1 and regulated upon expression normal T cell expressed and secreted (RANTES). Moreover, I/R injury led to an increase in phosphorylation (activation) of extracellular signal-regulated kinases 1/2 in the kidney; treatment with A438079 diminished this response. Collectively, these results indicate that early P2X7R inhibition is effective against renal tubule injury and proinflammatory response after I/R injury and suggest that targeting P2X7R may be a promising therapeutic strategy for treatment of AKI.
authors.affiliation: Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
authors.forename: Jianwen
authors.initials: J
authors.lastname: Bai
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and.
authors.forename: Chunming
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tolbert
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and.
authors.forename: George
authors.initials: G
authors.lastname: Bayliss
authors.affiliation: Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and.
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island.
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
authors.affiliation: Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and szhuang@lifespan.org.
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010766:Phosphorylation; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D034622:RNA Interference; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D064804:Urological Agents / Q000494:pharmacology*
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D000209:Acute-Phase Proteins; C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018836:Inflammation Mediators; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; C546469:P2rx7 protein, mouse; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles; D064804:Urological Agents; C071332:Lcn2 protein, mouse; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: acute kidney injury; apoptosis; purinergic receptors; renal tubular cells