Enhanced protection from renal ischemia: Reperfusion injury with A2A-adenosine receptor activation and PDE 4 inhibition

Okusa, Mark D.; Linden, Joel; Huang, Liping; Rosin, Diane L.; Smith, David F.; Sullivan, Gail M.

doi:10.1046/j.1523-1755.2001.0590062114.x

Cited by 32 publications

(49 citation statements)

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“…In addition, activation of A2a has been implicated in mediating anti-inflammatory effects and tissue protection (19). Consistent with this, A2a gene-deficient mice exhibit enhanced ischemia reperfusion-induced tissue damage in kidney and liver (20,21). Activation of A2a by selective receptor agonists has been shown to reduce tissue damage and maintain organ function in models of cardiac (22), renal (23), and pulmonary (24) ischemia reperfusion injury.…”

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confidence: 76%

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

Reutershan

Cagnina

Chang

et al. 2007

The Journal of Immunology

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117

119

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To determine the role of the adenosine receptor A2a in a murine model of LPS-induced lung injury, migration of polymorphonuclear leukocytes (PMNs) into the different compartments of the lung was determined by flow cytometry, microvascular permeability was assessed by the extravasation of Evans blue, and the release of chemotactic cytokines into the alveolar airspace was determined by ELISA. Measurements were performed in wild-type and A2a gene-deficient mice (A2a−/−). To differentiate the role of A2a on hemopoietic and nonhemopoietic cells, we created chimeric mice by transfer of bone marrow (BM) between wild-type and A2a−/− mice and used mice that lacked A2a expression selectively on myeloid cells (A2aflox/flox × LysM-cre). A specific A2a receptor agonist (ATL202) was used to evaluate its potential to reduce lung injury in vivo. In wild-type mice, therapeutic treatment with ATL202 reduced LPS-induced PMN recruitment, and release of cytokines. Pretreatment, but not posttreatment, also reduced Evans blue extravasation. In the BM chimeric mice lacking A2a on BM-derived cells, PMN migration into the alveolar space was increased by ∼50%. These findings were confirmed in A2aflox/flox × LysM-cre mice. ATL202 was only effective when A2a was present on BM-derived cells. A2a agonists may be effective at curbing inflammatory lung tissue damage.

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confidence: 76%

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

Reutershan

Cagnina

Chang

et al. 2007

The Journal of Immunology

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117

119

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“…The phosphodiesterase inhibitors olprinone 29,30 and rolip- BASIC RESEARCH www.jasn.org ram 31 improve renal function and reduce inflammation after IR injury. Anas et al 30 attribute this effect to a cAMP-PKA-or p38 MAPK-mediated decrease of NF-B activity and IL-8 expression.…”

Section: Discussionmentioning

confidence: 99%

Epac-Rap Signaling Reduces Cellular Stress and Ischemia-induced Kidney Failure

Stokman

Qin

Genieser

et al. 2011

Journal of the American Society of Nephrology

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Renal ischemia-reperfusion injury is associated with the loss of tubular epithelial cell-cell and cell-matrix interactions which contribute to renal failure. The Epac-Rap signaling pathway is a potent regulator of cell-cell and cell-matrix adhesion. The cyclic AMP analogue 8-pCPT-2Ј-O-Me-cAMP has been shown to selectively activate Epac, whereas the addition of an acetoxymethyl (AM) ester to 8-pCPT-2Ј-O-MecAMP enhanced in vitro cellular uptake. Here we demonstrate that pharmacological activation of Epac-Rap signaling using acetoxymethyl-8-pCPT-2Ј-O-Me-cAMP preserves cell adhesions during hypoxia in vitro, maintaining the barrier function of the epithelial monolayer. Intrarenal administration in vivo of 8-pCPT-2Ј-O-Me-cAMP also reduced renal failure in a mouse model for ischemia-reperfusion injury. This was accompanied by decreased expression of the tubular cell stress marker clusterin-␣, and lateral expression of ␤-catenin after ischemia indicative of sustained tubular barrier function. Our study emphasizes the undervalued importance of maintaining tubular epithelial cell adhesion in renal ischemia and demonstrates the potential of pharmacological modulation of cell adhesion as a new therapeutic strategy to reduce the extent of injury in kidney disease and transplantation.

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“…20 We tested whether A 2A R activation in podocytes by ATL313 regulated cAMP accumulation. ATL313 (50 nM) increased intracellular cAMP production from a baseline of 55 Ϯ 4 to 91 Ϯ 14 pmol/ml (P Ͻ 0.05), an effect completely blocked by ZM241385 (150 nM; 34 Ϯ 3 pmol/ml; P Ͻ 0.01 to ATL313).…”

Section: Atl313 Increases Podocyte Camp Levels In Vitromentioning

confidence: 99%

Activation of Adenosine 2A Receptors Preserves Structure and Function of Podocytes

Awad

Rouse

Liu

et al. 2008

Journal of the American Society of Nephrology

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Adenosine 2A receptor (A 2A R) activation was recently shown to be renoprotective in diabetic nephropathy. A 2A R are found in glomeruli and have been shown to associate with the podocyte cytoskeletal protein ␣-actinin-4, but the effect of their activation on podocyte structure and function is unknown. Podocyte injury was induced in C57BL/6 mice with puromycin aminonucleoside, and the selective A 2A R agonist ATL313 was found to attenuate the resulting albuminuria and foot process fusion. The selective A 2A R antagonist ZM241385 reversed the effects of ATL313. In vitro, A 2A R mRNA and protein were expressed in a conditionally immortalized podocyte cell line, and A 2A R-like immunoreactivity co-localized with the actin cytoskeleton. Treatment with ATL313 also blocked the increased podocyte permeability to albumin and disruption of the actin cytoskeleton that accompanied puromycin aminonucleosideinduced injury in vitro. ATL313 was ineffective, however, in the presence of the A 2A R antagonist and in A 2A R-deficient podocytes. It was concluded that A 2A R activation reduces glomerular proteinuria, at least in part, by preserving the normal structure of podocyte foot processes, slit diaphragms, and actin cytoskeleton.

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Enhanced protection from renal ischemia: Reperfusion injury with A2A-adenosine receptor activation and PDE 4 inhibition

Abstract: We conclude that the combined infusion of ATL-146e and rolipram leads to enhanced renal tissue protection from ischemia-reperfusion by mechanisms that may include reduced neutrophil adherence/recruitment and release of reactive oxygen species.

Cited by 32 publications

References 0 publications

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

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

Epac-Rap Signaling Reduces Cellular Stress and Ischemia-induced Kidney Failure

Activation of Adenosine 2A Receptors Preserves Structure and Function of Podocytes

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