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且昂贵的。缺血性急性肾损伤 (AKI) 发生在多达三分之二的重症监护患者和五分之一的住院成人中，约有 170 万人患有 AKI 这些患者每年都会死亡。然而，AKI 的极高死亡率并不是由肾衰竭本身引起的。 流行病学和临床数据支持 AKI 相关的远端器官功能障碍在贫困人群中的关键作用 AKI 的结果和死亡率。 AKI 还可导致慢性肾脏病 (CKD)，CKD 进展为 终末期肾病（ESRD）和肾移植失败。虽然 AKI 和 CKD 很繁重，但过渡 终末期肾病 (ESRD) 可能特别危险；退伍军人的死亡率 (~40%) 在入伍后的前 90 天内很高 ESRD 护理。 AKI 目前尚无治疗方法；因此，有效的 AKI 治疗是一个重要的未满足的医疗需求。 对肾缺血的强烈、迅速的炎症和氧化应激反应已得到很好的证实 由其他人和我们记录。肾缺血后还发现远端器官出现炎症， 但受伤的肾脏和远端器官之间的“串扰”也尚不清楚。有功绩 审查资金，我们已经证明了基于成体细胞的疗法在多种模型中的有效性 肾功能衰竭。鉴于相对较少的细胞具有巨大的好处，我们假设细胞外囊泡（EV 或 外泌体）是一种非病毒生物制品，从移植细胞中释放出来，是治疗效应物。我们发现 肾 EV 比原始细胞更有效，可以减少炎症和氧化应激， 改善缺血后的肾功能，即使是在肾功能衰竭后给予。其他人有 EV 在肾损伤模型中显示出益处。我们现在建议定义抗炎和抗氧化 肾EV对肾脏和远端器官的影响并确定具体的治疗药物。 我们的长期目标是开发有效的疗法来改善退伍军人的治疗结果 肾损伤。我们在该提案中的目标是定义关键的益处调节因素（包括抗炎药） 和抗氧化分子）在肾脏和远端器官中，通过 EV 得到改善并确定 电动汽车货物中的“活性成分”。我们的中心假设是肾 EV 为以下疾病提供了多方面的治疗： 肾缺血损伤，增加肾超氧化物和过氧化氢酶以及抗炎细胞因子和皮肤 和血小板 EV 不能减轻炎症，也没有保护作用。这将使我们能够定义具体的 肾EV中的有益货物。我们将利用空间转录组学的强大技术来检查 缺血引起的变化和 EV 的改善。此外，我们假设系统性和远程器官 炎症是由缺血而非尿毒症引起的，可以通过 EV 得到改善。根据我们的初步 根据数据，我们提出以下目标，以填补肾损伤和保护机制方面的知识空白： 1. 确定不同来源的细胞外囊泡对缺血后肾功能的功效， 炎症和氧化应激。初步数据支持肾脏 EV 的功效，但不支持血小板或皮肤 EV 的功效。 我们将研究提高疗效的方法（包括缺血预处理）。我们也会比较 有益肾EV和无效EV之间的货物和对缺血性损伤途径的影响 以确定基本的治疗成分和肾损伤的大多数改变途径。 2. 确定肾缺血对远端器官炎症和氧化应激的影响 EV 对肾缺血后炎症和器官功能的影响。 在这项工作结束时，我们希望能够定义关键的炎症和氧化应激 缺血性肾损伤的介质、肾缺血对远端器官炎症的影响、其他 改善缺血后和 EV 货物改善炎症和肾功能的具体机制。 预计结果将产生重大的积极影响，因为它们将提供强有力的证据—— 基于原理证明进一步开发潜在疗法以改善 AKI 的结果。