We previously demonstrated the anti-inflammatory effects and renal tissue protection in response to adenosine A 2A -receptor (A 2A R) activation in acute renal injury. We sought to extend these studies and determine the efficacy of A 2A R 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 2A knockout (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 2A R 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 Address for reprint requests and other correspondence: M. D. Okusa, Division of Nephrology, Box 133, Univ. of Virginia Health System, Charlottesville, VA 22908 (e-mail: mdo7y@virginia.edu )
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Adenosine A2A receptor activation attenuates inflammation and injury in diabetic nephropathy
Awad, Alaa S.; Huang, Liping; Ye, Hong; Duong, Elizabeth Thu Anh; Bolton, W. Kline; Linden, Joel; Okusa, Mark D.
Follow AJP - Renal Physiology
, Volume 290 (4): F828
The American Physiological Society – Apr 1, 2006
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