Acute renal failure (ARF) is associated with high morbidity and mortality. We are studying a model of renal ischemia/reperfusion (I/R) injury to examine mechanisms responsible for our new observation of a striking protective action of agonists of A2A-adenosine receptors (A2A-AR), compounds that inhibit inflammation. We have detected A2A-ARs on several different inflammatory cell types (neutrophils, monocytes and mast cells). The rationale for the proposed studies stems from our preliminary data and a large body of published data that suggest that activation of A2A-ARs dramatically reduces tissue injury, at least in part by reducing inflammation. Accordingly, we hypothesize that following renal I/R, selective A2A-AR agonists protect kidneys from tissue injury during early reperfusion by inactivating neutrophils and/or reducing neutrophil-endothelial cell interaction thus abrogating, early in the cascade, inflammatory cytokine release.
Aim 1 tests the hypothesis that activation of A2A-ARs is causally linked to reduced renal injury following I/R. A2A-AR-knockout (KO) mice will be used to determine the causal link between A2A-ARs and renal injury. Furthermore because the long range goal of our studies is to pursue clinical trials in human acute ischemic renal injury, we will examine the optimal dose and window of administration of A2A-agonists.
Aim 2 uses in vivo studies to test the hypothesis that A2A-ARs expressed on neutrophils and/or endothelial cells are the cellular target(s) of and mediate the effect of A2A-agonist in renal tissue protection. Toward this end we will use bone marrow radiation chimeras in which the stem cells of congenic wild-type mice are reconstituted into A2A -KO mice, or vice versa. These results will define the causal relation between activation of A2A-ARs expressed on inflammatory cells and renal tissue protection from I/R injury.
Aim 3 describes in vitro studies to test the hypothesis that selective agonist activation of A2A-ARs expressed on inflammatory cells (neutrophils/monocytes) and/or endothelial cells modulates adherence, adhesion molecule synthesis and surface delivery of newly synthesized adhesion molecules. We will employ the methods of metabolic labeling and biotinylation to isolate newly synthesized surface proteins from human microvascular endothelial cells and neutrophils from WT and A2A -KO mice and humans. In summary, these studies will establish the cellular basis for the dramatic anti-inflammatory effect of agonists of A2A-AR in I/R injury and provide the foundation for therapeutic intervention in ARF and allograft preservation in human studies.
| Vincent, I S; Okusa, M D (2015) Adenosine 2A receptors in acute kidney injury. Acta Physiol (Oxf) 214:303-10 |
| Li, Li; Huang, Liping; Ye, Hong et al. (2012) Dendritic cells tolerized with adenosine A?AR agonist attenuate acute kidney injury. J Clin Invest 122:3931-42 |
| Chhabra, Preeti; Linden, Joel; Lobo, Peter et al. (2012) The immunosuppressive role of adenosine A2A receptors in ischemia reperfusion injury and islet transplantation. Curr Diabetes Rev 8:419-33 |
| Kinsey, Gilbert R; Huang, Liping; Jaworska, Katarzyna et al. (2012) Autocrine adenosine signaling promotes regulatory T cell-mediated renal protection. J Am Soc Nephrol 23:1528-37 |
| Rosin, Diane L; Okusa, Mark D (2011) Dangers within: DAMP responses to damage and cell death in kidney disease. J Am Soc Nephrol 22:416-25 |
| Sharma, Ashish K; LaPar, Damien J; Zhao, Yunge et al. (2011) Natural killer T cell-derived IL-17 mediates lung ischemia-reperfusion injury. Am J Respir Crit Care Med 183:1539-49 |
| Awad, Alaa S; Rouse, Michael D; Khutsishvili, Konstantine et al. (2011) Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. Kidney Int 79:1090-8 |
| Laubach, Victor E; French, Brent A; Okusa, Mark D (2011) Targeting of adenosine receptors in ischemia-reperfusion injury. Expert Opin Ther Targets 15:103-18 |
| Awad, Alaa S; Kinsey, Gilbert R; Khutsishvili, Konstantine et al. (2011) Monocyte/macrophage chemokine receptor CCR2 mediates diabetic renal injury. Am J Physiol Renal Physiol 301:F1358-66 |
| Kinsey, Gilbert R; Okusa, Mark D (2011) Pathogenesis of acute kidney injury: foundation for clinical practice. Am J Kidney Dis 58:291-301 |
Showing the most recent 10 out of 38 publications
