Anti-inflammatory actions of exosomes in the postischemic kidney

缺血性肾损伤是常见的，导致急性肾损伤(AKI)，有助于 慢性肾脏病流行及其他病因慢性肾脏病进展至终末期 肾脏疾病和移植功能障碍。多达三分之二的重症监护患者会发生急性心肌梗死 全世界每五个住院的成年人中就有一个，但目前还没有有效的治疗方法。不幸的是， 几十年来，死亡率并没有显著改善。因此，需要新的方法。尽管 在理解病理生理学和肾脏替代疗法方面取得了重大进展，AKI是 与令人无法接受的高死亡率有关。我们和其他人已经记录了 肾缺血后损伤的炎症反应。此外，我们还发现外切体 可改善肾功能、结构、炎症和氧化应激，即使在服用后也是如此 肾功能衰竭已确定。肾脏炎症的机制和外切体的益处， 然而，人们对此还没有很好的理解。这项提案旨在通过审查以下方面的影响来填补这些空白 不同来源的外切体对缺血后肾脏炎症和氧化应激的影响。 我们的长期目标是开发有效的治疗方法，以改善急性胰腺炎的预后 肾损伤。这项应用的目的是确定肾脏外切体的机制 减少缺血/再灌注损伤后的炎症和氧化应激。我们的中央 假说是肾脏外切体为肾脏缺血性损伤提供了多方面的治疗， 增加肾脏超氧化物歧化酶、过氧化氢酶和抗炎细胞因子。此外，我们假设 皮肤和血小板外切体不具有保护性，这使我们能够定义特定的益处 外体货物。基于我们的初步数据，我们提出了以下目标，很好地应用于 已建立的模式： 1.确定不同来源的外切体对缺血后、肾功能、 炎症和氧化应激。 2.确定外切体在低氧致炎症转化中的作用 肾小管和血管内皮细胞处于一个多因素可控的系统中。 3.比较保护性和抗氧化性药物的抗炎抗氧化作用。 无效外切体，包括肾脏、皮肤、血小板和间充质干细胞外切体。 在这项工作结束时，我们预计已经定义了关键的炎症和氧化 缺血性肾损伤的应激介质和改善功能的外体货物。结果是 预计将产生重大的积极影响，因为它们将提供强有力的证据基础 进一步开发潜在疗法以改善AKI结果的原则证明。

Ischemic renal injury is common, causes acute kidney injury (AKI), contributes to the epidemic of chronic kidney disease (CKD) and progression of CKD of other etiologies to end stage renal disease and to transplant dysfunction. AKI occurs in up to two thirds of intensive care patients and 1 in 5 hospitalized adults worldwide, yet there is currently no effective therapy. Unfortunately, mortality has not improved significantly in decades. Thus, new approaches are needed. Despite large advances in understanding pathophysiology, and in renal replacement therapy, AKI is associated with unacceptably high mortality. We and others have documented the role of inflammatory responses in injury following renal ischemia. In addition, we have found that exosomes can improve renal function, structure, inflammation and oxidative stress, even when given after renal failure is established. The mechanisms of renal inflammation and benefit with exosomes, however, are not well understood. This proposal aims to fill those gaps by examining the effects of exosomes from different sources on inflammation and oxidative stress in the postischemic kidney. Our long-term goal is the development of effective therapies to improve outcomes in acute kidney injury. The objective of this application is defining the mechanisms by which renal exosomes decrease inflammation and oxidative stress following ischemia/reperfusion injury. Our central hypothesis is that renal exosomes provide a multi-faceted therapy for renal ischemic injury, increasing renal superoxide and catalase and anti-inflammatory cytokines. Furthermore, we posit that skin and platelet exosomes are not protective, allowing us to define specific beneficial exosomal cargo. Based on our preliminary data, we propose the following aims, employing out well established model: 1. To define the efficacy of exosomes from different sources on postischemic, renal function, inflammation and oxidative stress. 2. To determine the effect of exosomes on the proinflammatory transformation of hypoxic kidney tubular and endothelial cells in a system in which many factors can be controlled. 3. To compare cargo and the anti-inflammatory and anti-oxidation effects of protective and ineffective exosomes, including renal, skin, platelet and mesenchymal stem cell exosomes. At the conclusion of this work, we expect to have defined the key inflammatory and oxidative stress mediators of ischemic renal injury and the exosomal cargo that improve function. The results are expected to have a significant positive impact in that they will provide the strong evidence-based proof of principle for further development of potential therapies to improve outcomes in AKI.