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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.

Studies A[sub2A] adenosine receptor-mediated inhibition of renal injury and neutrophil adhesion. Reduction of neutrophil density in outer medulla of rats with A[sub2A] adenosine receptor activation; Influence of A[sub2A] adenosine receptors on renal tissue injury when administered to animals subjected to ischemia/reperfusion.

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

Investigates whether selective alpha2A adenosine receptor activation reduces ischemia-reperfusion injury in the rat kidney. Effect of adenosine on neutrophils and endothelial cells; Reduction in tubular injury and ischemic necrosis after ischemia-reperfusion injury following treatment with the adenosine analog DWH-146e.

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.

Examines the influence of polarization of receptor expression on the activity of their effector molecule, adenylyl cyclase. What immunohistochemistry and Western blot analysis confirmed; Assessment of adenylyl cyclase activity; Concluding remarks.

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.

DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/ reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important anti-inflammatory molecule in tissue inflammation, and adenosine 2A receptor (A2AR) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with A2AR-deficient DCs are more susceptible to kidney IRI and are not protected from injury by A2AR agonists. In addition, administration of DCs treated ex vivo with an A2AR agonist protected the kidneys of WT mice from IRI by suppressing NKT production of IFN-γ and by regulating DC costimulatory molecules that are important for NKT cell activation. A2AR agonists had no effect on DC antigen presentation or on Tregs. We conclude that ex vivo A2AR-induced tolerized DCs suppress NKT cell activation in vivo and provide a unique and potent cell-based strategy to attenuate organ IRI. [ABSTRACT FROM AUTHOR]

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]

Background: Renal interstitial inflammation is a consequence of unilateral ureteral obstruction (UUO). Following ischemia/reperfusion, adenosine reduces renal inflammation and injury, effects which are potentiated by type 4 phosphodiesterase inhibitors. We therefore studied the effects of A2A adenosine receptor agonist (ATL146e), and PDE4 inhibitor (rolipram) in mice subjected to UUO. Methods: Mice were subjected to UUO or sham operation, and received either vehicle or ATL146e + rolipram by osmotic minipump for 1 or 7 days. At 1, 3, 7, or 14 days after operation, renal macrophage infiltration, apoptosis, proliferation, tubular atrophy, and interstitial fibrosis were quantitated, and expressions of IL-6 and TGF-β mRNA were determined. Results: ATL146e + rolipram reduced macrophage infiltration by 40% after 3 days UUO (p < 0.05). Tubular apoptosis, tubular atrophy, and interstitial fibrosis were increased by 7 or 14 days UUO, but were unaffected by ATL146e + rolipram. However, cellular proliferation was increased by ATL146e + rolipram in the obstructed kidney. ATL146e + rolipram had no effect on the renal expression of IL-6 and TGF-β mRNA. Conclusions: A2A receptor activation and PDE4 inhibition transiently reduce renal macrophage infiltration, but do not ameliorate the renal response to UUO. We speculate that the persistent stimulus for inflammation triggered by UUO cannot be reversed by agents that suppress inflammatory cell activation alone. Copyright © 2005 S. Karger AG, Basel [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.

Activation of A[sub2A] adenosine receptors (A[sub2A]Rs) protects kidneys from ischemia-reperfusion injury (IRI). A[sub2A]Rs are expressed on bone marrow-derived (BM-derived) cells and renal smooth muscle, epithelial, and endothelial cells. To measure the contribution of A[sub2A]Rs on BM-derived cells in suppressing renal IRI, we examined the effects of a selective agonist of A[sub2A]Rs, ATL146e, in chimeric mice in which BM was ablated by lethal radiation and reconstituted with donor BM cells derived from GFP, A[sub2A]R-KO, or WT mice to produce GFP → WT, A[sub2A]-KO → WT, or WT → WT mouse chimera. We found little or no repopulation of renal vascular endothelial cells by donor BM with or without renal IRI. ATL146e had no effect on IRI in A[sub2A]-KO mice or A[sub2A]-KO → WT chimera, but reduced the rise in plasma creatinine from IRI by 75% in WT mice and by 60% in WT → WT chimera. ATL146e reduced the induction of IL-6, IL-β, IL-1ra, and TGF-α mRNA in WT → WT mice but not in A[sub2A]-KO → WT mice. Plasma creatinine was significantly greater in A[sub2A]-KO than in WT mice after IRI, suggesting some renal protection by endogenous adenosine. We conclude that protection from renal IRI by A[sub2A]R agonists or endogenous adenosine requires activation of receptors expressed on BM-derived cells. [ABSTRACT FROM AUTHOR]

Activation of A2A adenosine receptors (A2ARs) protects kidneys from ischemia-reperfusion injury (IRI). A2ARs are expressed on bone marrow-derived (BM-derived) cells and renal smooth muscle, epithelial, and endothelial cells. To measure the contribution of A2ARs on BM-derived cells in suppressing renal IRI, we examined the effects of a selective agonist of A2ARs, ATL146e, in chimeric mice in which BM was ablated by lethal radiation and reconstituted with donor BM cells derived from GFP, A2AR-KO, or WT mice to produce GFP-->WT, A2A-KO-->WT, or WT-->WT mouse chimera. We found little or no repopulation of renal vascular endothelial cells by donor BM with or without renal IRI. ATL146e had no effect on IRI in A2A-KO mice or A2A-KO-->WT chimera, but reduced the rise in plasma creatinine from IRI by 75% in WT mice and by 60% in WT-->WT chimera. ATL146e reduced the induction of IL-6, IL-1beta, IL-1ra, and TGF-alpha mRNA in WT-->WT mice but not in A2A-KO-->WT mice. Plasma creatinine was significantly greater in A2A-KO than in WT mice after IRI, suggesting some renal protection by endogenous adenosine. We conclude that protection from renal IRI by A2AR agonists or endogenous adenosine requires activation of receptors expressed on BM-derived cells. [ABSTRACT FROM AUTHOR]