Lymphangiogenesis in the pathogenesis of Acute Kidney Injury

急性肾损伤发病机制中的淋巴管生成

• 批准号: 10046290
• 负责人: ANUPAM AGARWAL
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046290
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Bilateral; Blocking Antibodies; CD44 Antigens; Cell Surface Receptors; Cells; Chronic Kidney Failure; Clinical; Clinical Trials; Complication; Critical Illness; Data; Data Reporting; Development; Dialysis procedure; Disease; Endothelium; Epithelial Cells; Fibrosis; Fluid Balance; Galectin 3; Goals; Health; Hospitalization; Impairment; Inflammation; Inflammatory; Injury; Injury to Kidney; Intensive Care Units; Ischemia; Kidney; Knockout Mice; Knowledge; Link; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; Magnetic Resonance Imaging; Mediating; Modality; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Myocardial Ischemia; Operative Surgical Procedures; Organ; Participant; Pathogenesis; Pathologic; Patients; Phase; Proteins; Recombinant Vascular Endothelial Growth Factor; Recovery; Renal Replacement Therapy; Reperfusion Injury; Reperfusion Therapy; Resolution; Risk; Role; Serum; Severities; Structure; Supportive care; Testing; Therapeutic Intervention; Transgenic Mice; Tubular formation; Up-Regulation; Ureteral obstruction; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factors; Veterans; conditional knockout; density; design; immune function; injury and repair; injury recovery; kidney fibrosis; lipid transport; lymphatic vessel; medical complication; mortality; receptor; recombinase-mediated cassette exchange; tissue repair

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. 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 lymphatic system is crucial for maintaining fluid balance, transporting lipids, and aiding in immune function. During pathological conditions that involve inflammation such as would occur in AKI and the AKI to CKD transition, these functions of the lymphatic system are further accentuated. Inflammation induces lymphangiogenesis through expression of vascular endothelial growth factors (VEGFs), particularly VEGF-C, VEGF-D, and their receptor VEGF-R3. New lymphatic vessels can then aid in transition of inflammatory cells, removing the cellular debris from the microenvironment of inflammation-induced injury, draining the excess fluid and ultimately facilitating tissue repair. While recent studies have shown lymphangiogenesis to be an active participant in a number of inflammatory diseases, very little is known about the role of the lymphatic system and more importantly, lymphangiogenesis, in the pathogenesis of AKI and the AKI to CKD transition. Our preliminary data demonstrate a significant upregulation of lymphangiogenic markers along with increased lymphatic vessel density during AKI. Our central hypothesis is that inflammation associated lymphangiogenesis (IAL), regulated by VEGF-C expression in myeloid and proximal tubule cells, is involved in the resolution of inflammation following AKI and the AKI to CKD transition. The aims of this proposal are designed to 1) determine how lymphangiogenesis modulates AKI; 2) determine how lymphangiogenesis affects the AKI to CKD transition; and 3) determine the cross-talk between the proximal tubule and myeloid cells in regulating lymphangiogenesis, inflammation, and AKI. Successful completion of the aims of this project will help elucidate the underlying mechanisms involved in the pathogenesis of AKI during both injury and the recovery phases and have the potential to provide new avenues for therapeutic interventions in AKI.

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）。许多治疗干预措施 在临床试验中进行了评估，以克服这一重大的临床挑战，但没有一个被证明是成功的。 该提案的总体目标是通过发现新的目标来填补这一知识空白， 用于阿基的治疗干预。 淋巴系统对于维持体液平衡、运输脂质和帮助免疫系统的功能至关重要。 功能在涉及炎症的病理状况期间，例如在阿基中会发生的炎症，并且阿基可引起炎症。 在慢性肾脏病的转变中，淋巴系统的这些功能进一步加重。炎症诱导 通过表达血管内皮生长因子（VEGF），特别是VEGF-C， VEGF-D及其受体VEGF-R3。新的淋巴管可以帮助炎症细胞的转移， 从炎症诱导的损伤的微环境中去除细胞碎片， 并最终促进组织修复。虽然最近的研究表明淋巴管生成是一个 淋巴结是许多炎症性疾病的积极参与者，但对淋巴结的作用知之甚少。 系统，更重要的是，淋巴管生成，在阿基的发病机制和阿基到CKD的转变。 我们的初步数据表明，淋巴管生成标记物沿着的增加， 淋巴管密度。 我们的中心假设是炎症相关的淋巴管生成（IAL），由 VEGF-C在髓样和近曲小管细胞中的表达，参与了以下炎症的消退： 阿基和阿基向CKD的转变。 本提案的目的是：（1）确定如何 2）确定淋巴管生成如何影响阿基向CKD的转变; 和3）确定近端小管和髓样细胞之间的串扰， 淋巴管生成、炎症和阿基。成功完成该项目的目标将有助于 阐明在损伤和恢复期间阿基发病机制的潜在机制 阶段，并有可能为阿基的治疗干预提供新的途径。