Adenosine A_2Areceptor 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.

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

“…23 Studies about the role of AR in the progression of DN in rats have attributed to the A 2A subtype, a possible protective role in preventing inflammation-associated renal injury, 24 while a controversial role has been attributed to A 1 subtype in mediating glomerular hyperfiltration. 25,26 We have determined that the nucleoside adenosine is a regulator of the VEGF production in glomeruli of rat in vitro.…”

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

“…These studies were carried out in Sprague-Dawley rats that were treated with the selective Adora2a agonist ATL146e. 56 Indeed, a serious of previous investigations from the laboratory of Dr. Okusa had shown that activation of Adora2a receptors on T cells provides protection during acute ischemic kidney disease. 2,3,21,22,57,58 As such, it is conceivable that Adora2a receptors expressed on inflammatory cells and vascular Adora2b receptors function together to protect the kidneys during diabetic nephropathy.…”

Therapeutic Anti-Inflammatory Effects of Myeloid Cell Adenosine Receptor A2a Stimulation in Lipopolysaccharide-Induced Lung Injury

“…Detrimental effects have been described in a model of cerebral ischemia where A2a activation on BM-derived cells led to increased brain tissue damage (47). However, in most other models, anti-inflammatory effects of A2a agonists predominate (38,48).…”