Lymphangiogenesis in the pathogenesis of Acute Kidney Injury

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)。许多治疗干预措施都有 已在临床试验中进行评估，以克服这一重大的临床挑战，但没有一项被证明是成功的。 这项提议的总体目标是通过发现新的目标来填补这一知识缺口 被用于AKI的治疗干预。 淋巴系统对维持液体平衡、输送脂质和帮助免疫至关重要。 功能。在涉及炎症的病理条件下，如AKI和AKI会发生 CKD的转变，淋巴系统的这些功能被进一步强调。炎症诱发 通过表达血管内皮生长因子(VEGFs)，特别是血管内皮生长因子-C(VEGF-C)来实现淋巴管的生成 血管内皮生长因子D及其受体血管内皮生长因子R3。然后，新的淋巴管可以帮助炎症细胞的转变， 清除炎症损伤微环境中的细胞碎片，排出多余的细胞碎片 液体，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种 积极参与多种炎症性疾病，对淋巴管的作用知之甚少 系统，更重要的是淋巴管生成，在AKI的发病机制和AKI向CKD的转变中起重要作用。 我们的初步数据显示淋巴管生成标记物显著上调 急性心肌梗死时淋巴管密度。 我们的中心假设是炎症相关淋巴管生成(IAL)，由 血管内皮生长因子-C在髓样细胞和近端小管细胞中的表达参与了炎症的消退 Aki和AKI向CKD的过渡。 这项提案的目的是1)决定如何 淋巴管生成调节AKI；2)确定淋巴管生成如何影响AKI向CKD的转变； 3)确定近端小管和髓系细胞在调节过程中的串扰 淋巴管生成、炎症和AKI。成功完成这个项目的目标将会有所帮助 阐明AKI在损伤和恢复过程中的发病机制 这是一个新的阶段，有可能为急性KI的治疗干预提供新的途径。

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.