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Am J Physiol Cell Physiol. 2015 Mar 15;308(6):C463-72. doi: 10.1152/ajpcell.00245.2014. Epub 2015 Jan 14.

P2X7 receptor inhibition protects against ischemic acute kidney injury in mice.

Author information

1
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.
2
Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
3
Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and.
4
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.
5
Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Providence, Rhode Island.
6
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.

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.

KEYWORDS:

acute kidney injury; apoptosis; purinergic receptors; renal tubular cells

PMID:
25588875
PMCID:
PMC4360025
DOI:
10.1152/ajpcell.00245.2014
[Indexed for MEDLINE]
Free PMC Article

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