Adenosine and Renal Injury

描述（由申请人提供）：糖尿病是美国终末期肾病（ESKD）最常见的病因，约占开始透析或移植时肾衰竭病例的40%。此外，糖尿病肾病（DN）与明显较高的发病率和死亡率相关。这些发现表明，慢性轻度炎症、ROS升高和内皮功能障碍在糖尿病并发症的肾脏发病机制中起核心作用。目前还没有新的治疗DN的选择，治疗依赖于肾素血管紧张素系统抑制剂的使用。需要新的治疗策略来预防糖尿病并发症。A2A -腺苷受体在肾脏和骨髓（BM）来源的细胞中表达，激活后可减轻炎症。我们已经证明，高选择性A2A -激动剂主要通过激活脑卒中来源细胞上的受体来减少与急性肾缺血再灌注损伤（IRI）相关的炎症。此外，我们的初步数据表明，在链脲佐菌素（STZ）诱导的糖尿病大鼠模型中，长期给药A2A -激动剂对减少肾损伤有深远的影响。因此，我们假设激活骨髓源性细胞上的A2A腺苷受体可以改善糖尿病肾病相关的肾损伤。另外，激活肾小球上皮细胞上表达的A2A -ARs可能会减少糖尿病肾病相关的损伤。为此目的：目的1验证了A2A -激动剂减少与糖尿病肾病相关的肾功能和形态学后果的假设。目的2验证了A2A Rs对脑源性细胞的激活介导组织保护的假设。目的3验证了激活A2A Rs可恢复DN足细胞完整性的假设。我们的实验方法将使用全动物、转基因小鼠、细胞培养和分子生物学来充分表征A2A -激动剂在DN中的保护作用，并确定A2A -激动剂在这种疾病中负责肾组织保护的细胞靶点。这类化合物有可能扩大抗炎A2A激动剂治疗的使用范围，从我们过去探索的急性用途，到更多的慢性用途，它们可能有很大的效用。这些实验也将揭示炎症在DN病因学中的作用，并为其他潜在的抗炎治疗策略提供见解。

DESCRIPTION (provided by applicant): Diabetes is the most common cause of end stage kidney disease (ESKD) in the United States, accounting for ~40% of the cases of renal failure at the time of initiation of dialysis or transplantation. Moreover diabetic nephropathy (DN) is associated with markedly higher morbidity and mortality rates. These finding points to the role of chronic mild inflammation, increased ROS and endothelial dysfunction as playing central roles in renal pathogenesis of diabetic complications. Currently no new options for the treatment of DN have been forthcoming and treatment relies on the use of inhibitors of the renin angiotensin system. Novel therapeutic strategies are needed to prevent complications of diabetes. A2A -adenosine receptors are expressed in kidney as well as bone marrow (BM) derived cells and upon activation reduce inflammation. We have demonstrated that highly selective A2A -agonists reduce inflammation associated with acute renal ischemia-reperfusion injury (IRI) primarily by activating receptors on BM-derived cell. Moreover our preliminary data demonstrate that A2A -agonists have profound effects to reduce renal injury when administered chronically in a rat model of streptozotocin (STZ)-induced diabetes. Therefore we hypothesize that activating A2A adenosine receptors on bone marrow-derived cells ameliorates renal injury associated with diabetic nephropathy. Alternatively activation of A2A -ARs expressed on glomerular epithelial cells may reduce injury associated with diabetic nehpropathy. To this end: Aim 1 tests the hypothesis that A2A -agonists reduce renal functional and morphological consequences associated with diabetic nephropathy. Aim 2 tests the hypothesis that activation of A2A Rs on BM-derived cells mediates tissue protection. Aim 3 tests the hypothesis that activation of A2A Rs restores podocyte integrity in DN. Our experimental approach will use whole animals, genetically altered mice, cell culture and molecular biology to fully characterize the protective effect of A2A -agonists in DN as well as to define the cellular targets of A2A -agonists that are responsible for renal tissue protection in this disorder. This class of compounds has the potential to extent the use of anti-inflammatory A2A agonist therapy from acute uses that we have explored in the past, to more chronic uses where they may have great utility. These experiments also will shed light on the role of inflammation in the etiology of DN and provide insights into other potential anti-inflammatory therapeutic strategies.