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We previously demonstrated the anti-inflammatory effects and renal tissue protection in response to adenosine A2A-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 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 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 < 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 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 < 0.001), whereas 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 and 2) causes reduced inflammation associated with diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Investigates the effect of A[sub 2A] adenosine receptors (A[sub 2A]AR) activation on protection of the liver from ischemia-reperfusion (I/R) injury and determines whether suppression of hepatic inflammatory chemokine production plays a role in this protection. Demonstration that the selective agonist of the A[sub 2a]AR produces a protection of wild-type C57BL/6 mice from liver I/R injury that is absent in congenic animals lacking the A[sub 2A]AR gene.

Focuses on the characteristics of the A[sub 2A] adenosine receptor and its potential in treating and preventing renal diseases. Pharmacology and molecular biology of receptors; Localization and functional effects of receptors in kidney; Comparative affinities of A[sub 2A] ligands for human adenosine receptor subtypes and signaling elements.

Discusses a study which determined the mechanisms responsible for the reduced renal tissue injury by agonists of adenosine receptors. Methods; Results; Discussion.

Presents information on a study which examined the effect of selective activation of A... adenosine receptors on ischemia-reperfusion injury in rat kidney. Methods of the study; Results and discussion.

Examine the influence of polarization of receptor expression on the activity of adenylyl cyclase. Alpha2B-adenosine receptor expression at the basolateral domain of LLC-PK1 cells; Effects of alpha2B-adrenergic receptor expression on cAMP accumulation in the LLC-PK1 cells; Polarized renal epithelial cell membrane characterized by domains differing functionally.