Protecting the kidney and remote organs following renal ischemia

肾缺血后保护肾脏和远端器官

• 批准号: 10369765
• 负责人: Katherine J Kelly
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369765
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Anti-Inflammatory Agents; Antiinflammatory Effect; Antioxidants; Bilateral; Biological; Blood Platelets; Caring; Cell Therapy; Cell Transplantation; Cells; Cessation of life; Chronic Kidney Failure; Clinical Data; Creatinine; Data; Depressed mood; Development; Disease; Disease Progression; Distant; Effectiveness; End stage renal failure; Epithelial Cells; Etiology; Failure; Functional disorder; Funding; Future; Goals; Health; Heart; Hour; Immune; Infiltration; Inflammation; Inflammatory; Injury; Injury to Kidney; Intensive Care; Ischemia; Ischemic Preconditioning; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knowledge; Liver; Lung; Malignant Neoplasms; Mediator of activation protein; Medical; Methods; Modeling; Organ; Outcome; Oxidants; Oxidative Stress; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Phenotype; Rattus; Recovery; Renal function; Role; Skin; Source; Structure; Superoxides; Techniques; Therapeutic; Translations; Transplantation; Tubular formation; Veterans; Work; base; biological adaptation to stress; catalase; cytokine; effective therapy; epidemiologic data; evidence base; exosome; extracellular vesicles; heart function; improved; improved outcome; ischemic injury; meetings; mortality; pre-clinical; preservation; renal ischemia; transcriptomics

Ischemic injury to the kidney and other organs is deadly and expensive. Ischemic acute kidney injury (AKI) occurs in up to two thirds of intensive care patients and 1 in 5 hospitalized adults with ~1.7 million of these patients dying annually. The very high mortality in AKI, however, is NOT caused by renal failure per se. Epidemiological and clinical data support the critical role of AKI-associated distant organ dysfunction in poor outcomes and mortality in AKI. AKI also can result in chronic kidney disease (CKD), progression of CKD to end stage renal disease (ESRD) and kidney transplant failure. While AKI and CKD are onerous, the transition to ESRD can be particularly perilous; mortality rates in Veterans (~40%) are huge in the first 90 days of ESRD care. AKI has no current treatment; thus, effective AKI therapy is an important unmet medical need. The robust, prompt inflammatory and oxidative stress response to renal ischemia has been well documented by others and by us. Inflammation in remote organs has also been found after renal ischemia, but the “crosstalk” between the injured kidney and remote organs is also not well understood. With Merit Review funding, we have demonstrated the effectiveness of adult-cell based therapies in multiple models of renal failure. Given the large benefits of relatively few cells, we hypothesized that extracellular vesicles (EV or exosomes), a non-viral biologic, released from the transplanted cells were the therapeutic effector. We found that renal EV were more effective than the originating cells, decreasing inflammation and oxidative stress and improving renal function postischemia, even when given after renal failure was established. Others have shown benefit with EV in renal injury models. We now propose to define the anti-inflammatory and anti-oxid- ant effects of renal EV in the kidney and remote organs and determine the specific therapeutic cargo. Our long-term goal is the development of effective therapies to improve outcomes in Veterans with renal insults. Our objective in this proposal is defining key mediators of benefit (including anti-inflammatory and anti-oxidative molecules) in the kidney and remote organs that are improved by EV and determine the “active ingredients” in EV cargo. Our central hypotheses are that renal EV provide a multi-faceted therapy for renal ischemic injury, increasing renal superoxide and catalase and anti-inflammatory cytokines and that skin and platelet EV do not decrease inflammation and are not protective. This will allow us to define the specific beneficial cargo in renal EV. We will employ the powerful technique of spatial transcriptomics to examine the changes with ischemia and improvements with EV. Furthermore, we posit that systemic and remote organ inflammation result from ischemia and not uremia and can be improved with EV. Based on our preliminary data, we propose the following aims to fill knowledge gaps in the mechanisms of renal injury and protection: 1. To define the efficacy of extracellular vesicles from different sources on postischemic renal function, inflammation and oxidative stress. Preliminary data support efficacy of renal, but not platelet or skin EV. We will examine means (including ischemic preconditioning) to improve efficacy. We will also compare cargo and the effects on pathways of ischemic injury between beneficial renal EV and ineffective EV in order to define the essential therapeutic cargo components and most altered pathways of renal injury. 2. To determine the effect of renal ischemia on inflammation and oxidative stress in remote organs and the effect of EV on inflammation and organ function following renal ischemia. At the conclusion of this work, we expect to have defined the key inflammatory and oxidative stress mediators of ischemic renal injury, the effects of renal ischemia on inflammation in remote organs, other specific mechanisms of benefit postischemia and the EV cargo that improve inflammation and renal 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.

肾脏和其他器官的缺血性损伤是致命的急性肾脏损伤。 （AKI）最多三分之二的重症监护患者和五分之一的成年人中有三分之一发生。 这些患者死于ANKI中的死亡率很高，这不是肾衰竭引起的。 流行病学和临床数据支持AKI相关的远处器官功能障碍在差的关键作用 AKI的结果和死亡率也可能导致慢性肾脏疾病（CKD），CKD的进展 末期肾脏疾病（ESRD）和肾脏移植衰竭。 ESRD可能特别危险； ESRD护理。 对肾脏缺血的强大，迅速的炎症和氧化应激反应一直很好 在肾脏缺血之后，也发现了他人和我们的炎症。 但是，受伤的肾脏和远程器官之间的“ crostalk”也没有很好地理解。 审查资金，我们已经证明了基于成人的疗法在多种模型中的有效性 肾功能衰竭。我们假设相对较少的细胞的好处 外泌体），一种从移植细胞中释放的非病毒生物学是我们发现的Thetic效应子 肾脏EV是有效的原始细胞 即使在建立肾衰竭之后，还可以改善肾功能后的肾功能。 在肾脏损伤模型中显示了EV的好处。 肾脏EV在肾脏和远程器官中的蚂蚁影响，并确定特定的治疗货物。 我们的长期目标是在退伍军人中发展有效的治疗结果 肾脏侮辱。 肾脏和远程器官中的抗氧化分子）通过EV改进并确定您 EV货物中的“活性成分”。 肾脏缺血性损伤，增加肾氧化物，过氧化氢酶和抗炎细胞因子以及皮肤 血小板EV不会减少炎症，也不是保护。 肾脏EV中的有益货物。 通过缺血和EV的改进，我们认为该系统性和远程器官 炎症是由缺血而不是尿毒症引起的，并且可以根据我们的初步来改善。 数据，我们建议以下旨在填补肾脏损伤和保护机制的知识空白： 1。为了定义来自不同来源的细胞外囊泡的疗效，对缺血后肾功能， 炎症和氧化应激。 我们将检查手段（包括缺血性预处理）以提高效力。 货物以及对有益EV与无效EV之间缺血性损伤途径的影响 为了定义必需的治疗货物组件和肾脏损伤的最大途径。 2。确定肾脏缺血对偏远器官炎症和氧化应激的影响 肾脏缺血后的EV炎症和器官功能的影响。 在这项工作结束时，我们希望定义关键的炎症和氧化应激 缺血性肾脏损伤的介体，肾脏缺血对偏远器官炎症的影响，其他 益处的特定机制和改善炎症和肾功能的EV货物的特定机制。 预计结果将对强有力的证据产生重大积极影响 - 基于原则证明，以进一步开发潜在疗法以改善AKI的预后。