Adenosine A2A receptor activation attenuates inflammation and injury in diabetic nephropathy
AJP - Renal Physiology
Adenosine A 2A receptor activation attenuates inflammation and injury in diabetic nephropathy. We previously demonstrated the anti-inflammatory effects and renal tissue protection in response to adenosine A 2A-receptor (A2AR) 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
... omerular 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 ⅐ kg Ϫ1 ⅐ min Ϫ1 ), 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 with control (nephrin; P Ͻ 0.05 and podocin; P Ͻ 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-␣ (1,586% 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 knockout (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 Ͻ 0.001), whereas it had no effect on the A2A-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. proteinuria; diabetes; macrophage; kidney; ATL146e DIABETES MELLITUS IS the most common cause of end-stage renal disease (ESRD), responsible for more than 40% of all cases in the United States (1, 52), and this number is likely to continue to increase unabated. Current therapy, including blood pressure and glucose control and treatment with blockers of the reninangiotensin system, has been modestly successful in delaying the progression of renal failure. More robust outcomes might be achieved through interventions that reverse pathophysiological changes caused by diabetic nephropathy.