We previously demonstrated the anti-inflammatory effects and renal tissue protection in response to adenosine A_2A-receptor (A_2AR) activation in acute renal injury. We sought to extend these studies and determine the efficacy of A_2AR agonists in a chronic model of renal injury. We hypothesized that A_2A agonists mediate renal tissue protection in diabetic nephropathy by reducing glomerular inflammation. Diabetes was induced with single intravenous injection of streptozotocin 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⁻¹·min⁻¹), a selective A_2A agonist. The increase in UAE in the diabetes group was associated with a significant reduction in the expression of slit diaphragm-associated molecules compared with 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 monocyte chemoattractant protein-1 (705% of control), TNF-α (1,586% of control), IFN-γ (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 A_2Aknockout (A_2A-KO) mice. Four weeks after diabetes, UAE increased significantly in both WT and A_2A-KO diabetic mice (3.0- and 3.3-fold over control). A_2A agonist treatment blocked the increase in UAE in WT diabetic mice (P < 0.001), whereas it had no effect on the A_2A-KO diabetic mice. These results demonstrate that chronic A_2AR activation in diabetic rats 1) ameliorates histological and functional changes in kidneys induced by diabetes and 2) causes reduced inflammation associated with diabetic nephropathy.