Lymphangiogenesis in the pathogenesis of acute kidney injury

项目摘要 急性肾损伤(AKI)是内科和外科疾病的常见和严重并发症 在危重退伍军人中有显著的可归因性发病率和死亡率。退役军人健康状况分析 管理数据报告称，在住院期间患AKI的退伍军人有很大的风险 1年内发展为慢性肾脏病(CKD)。Aki也是一个主要的复杂问题 住院的新冠肺炎患者和近一半发生急性心肌梗死的患者无法恢复到基线 肾功能。许多治疗措施已经在临床试验中进行了评估，以克服这一点 重大的临床挑战，没有一个被证明是成功的。这项提议的总体目标是填补这一空白 通过发现可用于AKI治疗干预的新靶点，在知识方面取得进展。 这个项目的重点是淋巴系统，特别是肾脏中的淋巴管生成，将 在上一个供资周期取得进展的基础上再接再厉。淋巴管有助于炎性物质的运输 细胞，从炎症诱导的损伤微环境中清除细胞碎片，排出多余的 液体，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，肾脏淋巴系统在AKI和AKI到CKD发病机制中的作用 转型只是现在才被认识到。 我们最近的工作表明，淋巴管生成的主要配体血管内皮生长因子-C和血管内皮生长因子-D， 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AKI模型中，肾损伤后强烈诱导形成。我们的中心假设是 炎症相关淋巴管生成在AKI的发病机制和AKI的转化中的作用 致CKD。我们将从三个方面对这一总体假设进行检验。在目标1中，我们将检验假设 炎症相关淋巴管生成起源于预先存在的淋巴管内皮细胞 AKI后的肾脏。在目标2中，我们将检验一种假设，即髓系细胞维持的完整淋巴网络 AKI后，系细胞是维持肾脏结构和功能所必需的。在目标3中，我们将测试 LA依赖于急性脑损伤后淋巴管内皮细胞中NF-κB表达的假说 从AKI到CKD的过渡。 这些研究将对揭示淋巴管生成的机制产生重大影响 并为淋巴在AKI病理生物学中的动态功能提供了新的见解。成功后 完成建议的目标后，我们将全面研究淋巴管生成在 AKI和AKI到CKD的过渡，并将提供一个新的平台，将促进 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.