Anti-inflammatory actions of exosomes in the postischemic kidney

缺血性肾损伤是常见的，引起急性肾损伤（阿基），促成急性肾损伤。 慢性肾病（CKD）流行和其他病因的CKD进展至终末期 肾脏疾病和移植功能障碍。阿基发生在多达三分之二的重症监护患者中 全世界每5名住院成人中就有1人患有这种疾病，但目前尚无有效的治疗方法。不幸的是， 死亡率几十年来没有显著改善。因此，需要新的办法。尽管 在理解病理生理学和肾脏替代治疗方面取得了很大进展， 与不可接受的高死亡率有关。我们和其他人已经记录了 肾缺血损伤后的炎症反应。此外，我们发现外泌体 可以改善肾功能，结构，炎症和氧化应激，即使在 肾功能衰竭已确定。肾脏炎症的机制和外来体的益处， 然而，这些问题并没有得到很好理解。本提案旨在通过审查以下方面的影响， 来自不同来源的外泌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 肾损伤本申请的目的是定义肾外泌体通过其表达的机制。 减少缺血/再灌注损伤后的炎症和氧化应激。我们的中央 假设是肾外来体为肾缺血性损伤提供了多方面的治疗， 增加肾脏超氧化物和过氧化氢酶以及抗炎细胞因子。此外，我们 皮肤和血小板外泌体没有保护作用，这使我们能够确定特定的有益的 外泌体货物根据我们的初步数据，我们提出了以下目标， 建立模型： 1.为了确定来自不同来源的外来体对缺血后肾功能的功效， 炎症和氧化应激。 2.为了确定外泌体对缺氧的促炎性转化的影响， 肾小管和内皮细胞在一个系统中，其中许多因素可以控制。 3.比较货物和抗炎和抗氧化作用的保护和 无效的外泌体，包括肾脏、皮肤、血小板和间充质干细胞外泌体。 在这项工作的结论，我们希望已经确定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泌体货物。结果 预计将产生重大的积极影响，因为它们将提供强有力的基于证据的 进一步开发潜在疗法以改善阿基结局的原则证据。

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.