Lymphangiogenesis in the pathogenesis of acute kidney injury

项目摘要 急性肾损伤（阿基）是内科和外科疾病的常见且严重的并发症， 在危重退伍军人中有显著的归因发病率和死亡率。退伍军人健康分析 管理数据报告称，在住院期间发生阿基的退伍军人存在以下风险： 1年内发生慢性肾病（CKD）。阿基也是一种主要的并发症， 住院的COVID-19患者和近一半发生阿基的患者没有恢复到基线水平 肾功能许多治疗干预措施已在临床试验中进行了评估，以克服这一点 重大临床挑战，无一成功。这项提案的总体目标是填补这一空白 通过发现可用于阿基治疗干预的新靶点， 该项目的重点是淋巴系统，特别是肾脏中的淋巴管生成， 在上一个供资周期所取得进展的基础上再接再厉。淋巴管有助于炎性细胞的转运 细胞，从炎症诱导损伤的微环境中清除细胞碎片，排出过量的 并最终促进组织修复。虽然研究强调了淋巴管生成的关键作用， 在心脏中，肾脏中淋巴系统在阿基发病机制中的作用以及阿基对CKD的影响 过渡现在才被认识到。 我们最近的工作表明，VEGF-C和VEGF-D，淋巴管生成的主要配体， 在基线时大量存在于肾小管中，并在损伤后分泌。淋巴管 在多种阿基模型中，在肾损伤后强烈诱导形成。我们的核心假设是， 炎症相关的淋巴管生成在阿基的发病机制和阿基的转化中是有益的 到CKD。我们将从三个方面来检验这一总体假设。在目标1中，我们将检验以下假设： 炎症相关的淋巴管生成起源于血管内皮细胞中预先存在的淋巴管内皮细胞。 阿基后的肾脏。在目标2中，我们将检验由骨髓维持完整淋巴网络的假设 在阿基后，需要谱系细胞来保持肾结构和功能。在目标3中，我们将测试 假设LA依赖于阿基后淋巴管内皮细胞中NF-κB表达， 阿基向CKD的过渡。 这些研究将在揭示淋巴管生成机制方面产生重大影响， 并为阿基病理生物学中代谢物的动态功能提供了新的见解。一旦成功 完成拟议的目标，我们将全面审查淋巴管生成的作用， 阿基和阿基向CKD的过渡，还将提供一个新的平台， 在该领域的治疗努力。

Project Summary Acute kidney injury (AKI) is a common and serious complication of medical and surgical diseases that has significant attributable morbidity and mortality in critically ill Veterans. Analysis of Veterans Health Administrative data reported that Veterans who develop AKI during a hospitalization are at substantial risk for the development of chronic kidney disease (CKD) within 1 year. AKI is also a major complication of hospitalized COVID-19 patients and almost half of these patients who develop AKI do not recover to baseline kidney function. Numerous therapeutic interventions have been evaluated in clinical trials to overcome this significant clinical challenge, with none proven successful. The overall goal of this proposal is to fill this gap in knowledge by discovering new targets that could be exploited for therapeutic interventions in AKI. The focus of this project on the lymphatic system, specifically lymphangiogenesis in the kidney, will build upon the progress made during the previous funding cycle. Lymphatics aid in transport of inflammatory cells, removal of cellular debris from the microenvironment of inflammation-induced injury, drainage of excess fluid and ultimately facilitate tissue repair. While studies have highlighted the key role for lymphangiogenesis in the heart, the role of the lymphatic system in the kidney in the pathogenesis of AKI and the AKI to CKD transition is only now being recognized. Our recently work demonstrated that VEGF-C and VEGF-D, the major ligands in lymphangiogenesis, are abundantly present in renal tubules at baseline and are secreted following injury. Lymphatic vessel formation is robustly induced following kidney injury in multiple models of AKI. Our central hypothesis is that inflammation associated lymphangiogenesis is beneficial in the pathogenesis of AKI and the transition of AKI to CKD. We will test this overall hypothesis in three aims. In Aim 1, we will test the hypothesis that inflammation associated lymphangiogenesis originates from preexisting lymphatic endothelial cells in the kidney after AKI. In Aim 2, we will test the hypothesis that an intact lymphatic network maintained by myeloid lineage cells is required for preserving renal structure and function after AKI. In Aim 3, we will test the hypothesis that LA is dependent on NF-κB expression in lymphatic endothelial cells following AKI and during the AKI to CKD transition. These studies will have a significant impact both in uncovering mechanisms of lymphangiogenesis and providing new insights into the dynamic function of lymphatics in the pathobiology of AKI. Upon successful completion of the proposed aims, we will have comprehensively examined the role of lymphangiogenesis in AKI and the AKI to CKD transition, and will also provide a novel platform that will facilitate translational therapeutic efforts in the field.