Renal A2B Adenosine Receptors during ischemic preconditioning

在炎症/缺氧组织部位释放的细胞外核苷酸通过表面表达的外核苷酸酶代谢为腺苷并激活腺苷受体（AR）。几项研究暗示了细胞外腺苷在有限氧可用性条件下的组织保护中的重要作用。在这里，我们提出了初步的数据显示外核苷酸酶依赖的腺苷的产生和信号-特别是通过A2 BAR-在缺血预处理（IP）的肾脏保护。因此，提出了三个具体的目标，以进一步确定和功能表征缺血期间肾脏的A2 BAR依赖性组织保护机制。作为第一步，我们将确定肾脏A2 BAR的组织特异性定位及其在体内对缺血和IP的表达反应。基于这些研究，我们将利用体外肾脏缺氧和预处理模型来了解预处理过程中A2 BAR依赖的组织保护机制。最后，我们将定义在体内肾缺血期间靶向A2 BAR的策略。这些实验将促进在几个方面取得重大进展，包括对肾脏适应缺血/缺氧的先天机制的更基本的理解。此外，新的药理学方法，由肾缺血/缺氧沉淀的疾病，一个医学问题，从不同领域的医学和外科危重病人的发病率和死亡率。

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.