A1 adenosine receptor knockout mice exhibit increased renal injury following ischemia and reperfusion

Controversy exists regarding the effect of A(1) adenosine receptor (AR) activation in the kidney during ischemia and reperfusion (I/R) injury. We sought to further characterize the role of A(1) ARs in modulating renal function after I/R renal injury using both pharmacological and gene deletion approaches in mice. A(1) AR knockout mice (A(1)KO) or their wild-type littermate controls (A(1)WT) were subjected to 30 min of renal ischemia. Some A(1)WT mice were subjected to 30 min of renal ischemia with or without pretreatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) or 2-chrolo-cyclopentyladenosine (CCPA), selective A(1) AR antagonist and agonist, respectively. Plasma creatinine and renal histology were compared 24 h after renal injury. A(1)KO mice exhibited significantly higher creatinines and worsened renal histology compared with A(1)WT controls following renal I/R injury. A(1)WT mice pretreated with the A(1) AR antagonist or agonist demonstrated significantly worsened or improved renal function, respectively, after I/R injury. In addition, A(1)WT mice pretreated with DPCPX or CCPA showed significantly increased or reduced markers of renal inflammation, respectively (renal myeloperoxidase activity, renal tubular neutrophil infiltration, ICAM-1, TNF-alpha, and IL-1beta mRNA expression), while demonstrating no differences in indicators of apoptosis. In conclusion, we demonstrate that endogenous or exogenous preischemic activation of A(1) ARs protects against renal I/R injury in vivo via mechanisms leading to decreased necrosis and inflammation.