Renal A2B Adenosine Receptors during ischemic preconditioning

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Extracellular nucleotides liberated at inflammatory/hypoxic tissue sites are metabolized to adenosine by surface-expressed ecto-nucleotidases and activate adenosine receptors (ARs). Several studies implicate an important role of extracellular adenosine in tissue protection during conditions of limited oxygen availability. Here, we present preliminary data showing ecto-nucleotidase-dependent adenosine generation and signalling – particularly through the A2BAR – in renal protection during ischemic preconditioning (IP). Therefore, three specific aims are proposed to further identify and functionally characterize mechanisms of A2BAR-dependent tissue protection of the kidneys during ischemia. As first step, we will define the tissue-specific localization of the renal A2BAR and its expressional responses to ischemia and IP in vivo. Based on these studies, we will utilize in vitro models of renal hypoxia and preconditioning to understand A2BAR-dependent mechanisms of tissue protection during preconditioning. Finally, we will define strategies to target the A2BAR during renal ischemia in vivo. These experiments will facilitate significant progress on several fronts, including a more basic understanding of innate mechanisms of renal adaptation to ischemia/hypoxia. In addition, novel pharmacological approaches to diseases precipitated by renal ischemia/hypoxia would be made, a medical problem contributing to morbidity and mortality of critically ill patients from different fields of medicine and surgery.