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1 Department of Medicine, University of Virginia, Charlottesville, VA, USA
2 Department of Medicine, University of Virginia, Charlottesville, VA, USA; Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
* To whom correspondence should be addressed. E-mail: mdo7y{at}virginia.edu.
We previously demonstrated the anti-inflammatory effects and renal tissue protection in response to adenosine 2A-receptor (A2AR) activation in acute renal injury. We sought to extend these studies and determine the efficacy of A2AR-agonists in a chronic model of renal injury. We hypothesized that A2A-agonists mediate renal tissue protection in diabetic nephropathy by reducing glomerular inflammation. Diabetes was induced with single iv injection of streptozotocin (STZ) in Sprague Dawley rats (50 mg/kg). Increases in urinary albumin excretion (UAE) and plasma creatinine at week 6 in the diabetes group (26- and 6-fold over control, respectively) were markedly reduced by continuous subcutaneous administration of ATL146e (10 ng/kg/min), a selective A2A-agonist. The increase in UAE in the diabetes group was associated with a significant reduction in the expression of slit diaphragm-associated molecules compared to control (nephrin; P<0.05 and podocin; P<0.005) that was reversed by ATL146e treatment. Diabetes led to an increase in urinary excretion of MCP-1 (705% of control), TNF- 
(1586% of control), IFN-
(298% of control), kidney fibronectin mRNA (457% of control) and glomerular infiltration of macrophages (764% of control), effects significantly reduced by ATL146e treatment. Mesangial expansion and basement membrane thickness were reduced with ATL146e. To further confirm the selectivity of ATL146e, we used wild type (WT) or A2A knock-out (A2A-KO) mice. Four weeks after diabetes, UAE increased significantly in both WT and A2A-KO diabetic mice (3.0- and 3.3-fold over control). A2A-agonist treatment blocked the increase in UAE in WT diabetic mice (P<0.001) while it had no effect on the A2A-KO diabetic mice. These results demonstrate that chronic A2AR activation in diabetic rats: 1) ameliorates histological and functional changes in kidneys induced by diabetes; 2) causes reduced inflammation associated with diabetic nephropathy.
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