title: Adenosine A2A receptor activation attenuates inflammation and injury in diabetic nephropathy.
abstract: 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 x kg(-1) x 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-alpha (1,586% of control), IFN-gamma (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.
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, USA.
authors.forename: Alaa S
authors.initials: AS
authors.lastname: Awad
authors.forename: Liping
authors.initials: L
authors.lastname: Huang
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: Elizabeth Thu Anh
authors.initials: ET
authors.lastname: Duong
authors.forename: W Kline
authors.initials: WK
authors.lastname: Bolton
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
authors.forename: Mark D
authors.initials: MD
authors.lastname: Okusa
mesh_terms: D058908:Adenosine A2 Receptor Agonists; D000419:Albuminuria; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000276:immunology* / Q000503:physiopathology*; D007249:Inflammation; D007668:Kidney / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043683:Receptors, Adenosine A2 / Q000502:physiology*
chemical_list: C431129:ATL 146e; D058908:Adenosine A2 Receptor Agonists; D003509:Cyclohexanecarboxylic Acids; D011687:Purines; D043683:Receptors, Adenosine A2