lmmunomodulatory roles of renal lymphatic endothelial cells in Acute Kidney Injury

项目总结 在美国，估计有50%的ICU患者发生AKI，并与50%的死亡率RTE相关。 单一的AKI易使患者发展成慢性疾病，如慢性肾脏疾病 慢性肾脏病(CKD)和终末期肾病(ESRD)，这些疾病会降低生活质量，并可能是致命的。 越来越多的研究表明，AKI诱导的损伤会促进持续性的肾脏炎症和纤维化 推动进展为慢性肾脏病和终末期肾病。了解肾脏炎症可能通过的机制 因此，受监管将允许开发有针对性的肾脏治疗环境。炎症 相关的淋巴管生成负责通过摄取液体来维持组织的动态平衡， 大分子、蛋白质和免疫细胞的运输。AKI对淋巴生长因子血管的损伤 血管内皮细胞生长因子D(VEGF-D)和血管内皮细胞生长因子C在肾脏内升高。淋巴研究已经 已确定的LECs的免疫调节作用，如MHC、趋化因子受体和抗原的表达 演示文稿。实验室已证实AKI模型的肾脏淋巴管生成增加可改变适应性 免疫细胞的存在，减少肾脏纤维化。然而，LECs如何调节AKI相关性炎症 复苏仍是未知数。这项研究的长期目标是确定如何发挥免疫调节作用 LECs影响AKI患者的肾脏免疫反应和恢复。该提案的总体目标是确定如何 AKI患者的获得性免疫反应随着肾脏淋巴密度的增加而改变，以及这些免疫反应是如何 当已知的LEC免疫调节分子缺失时，细胞群会发生变化。中心假说 肾小管上皮细胞通过直接的淋巴-免疫细胞相互作用调节炎症和调节免疫 细胞从组织中清除，改变AKI的病理生理结果。由大力支持的导演 初步数据这一假设将通过两个具体目标进行检验：目标1确定肾脏如何增加 淋巴管生成改变AKI的获得性免疫反应。目标2演示LEC特异性删除 鞘氨醇-1-磷酸(S1P)的分泌改变了AKI患者的T细胞反应和炎症消退。在 首先，顺铂和急性肾损伤的缺血再灌注(IR)模型将评估肾淋巴管密度是否增加 小鼠肾脏损伤前特异性诱导的血管内皮生长因子-D(KidVD)过表达改变适应性改变 免疫细胞群与炎症进展。初步数据显示肾淋巴管增多 密度启动适应性免疫反应，减轻肾脏纤维化。对于第二个目标，确定 LEC特异性S1P的缺失如何改变肾脏免疫细胞清除和获得性免疫 AKI的反应可能提供一种新的肾脏靶向治疗选择。解决LEC如何监管AKI 相关的炎症和恢复淋巴特异的遗传模型，肾损伤模型， 免疫细胞表型将确定肾脏免疫细胞对AKI反应的变化。

PROJECT SUMMARY In the United States an estimated 50% of ICU patients develop AKI and is associated with a 50% mortality rte. A single occurrence of AKI predisposes a patient to develop chronic conditions such as Chronic Kidney Disease (CKD) and End-Stage Renal Disease (ESRD), conditions which decrease quality of life and may be fatal. Increasingly, research demonstrates that AKI induced injury promotes persistent renal inflammation and fibrosis driving progression to CKD and ESRD. Understanding mechanisms by which renal inflammation may be regulated would therefore allow development of targeted renal therapeutic environments. Inflammation associated lymphangiogenesis is responsible for maintaining tissue homeostasis through uptake of fluids, macromolecules, proteins, and immune cell trafficking. Upon AKI insult lymphatic growth factors Vascular endothelial growth factor D (VEGF-D) and VEGF-C are increased within the kidney. Lymphatic research has identified immunomodulatory roles of LECs such as expression of MHCs, chemokine receptors, and antigen presentation. The lab has demonstrated increased renal lymphangiogenesis in models of AKI alters adaptive immune cell presence and reduces renal fibrosis. However, how LECs regulate AKI associated inflammation and recovery is still unknown. The long-term goal of this study is to identify how immunomodulatory roles of LECs impact the renal immune response and recovery in AKI. The proposal’s overall objective is to identify how the adaptive immune response is altered in AKI with increased renal lymphatic density and how these immune cell populations are altered upon deletion of a known LEC immunomodulatory molecule. The central hypothesis is that renal LECs regulate inflammation through direct lymphatic-immune cell interactions and regulate immune cell clearance from the tissue, altering pathophysiological outcomes in AKI. Directed by strongly supportive preliminary data the hypothesis will be tested by two specific aims: Aim 1 Identify how increased renal lymphangiogenesis alters the adaptive immune response in AKI. Aim 2 Demonstrate LEC specific deletion of sphingosine-1-phosphate (S1P) secretion alters the T cell response and inflammation resolution in AKI. In the first aim cisplatin and ischemia-reperfusion (IR) models of AKI will assess if increased renal lymphatic density prior to injury in a mouse model of kidney specific inducible overexpression of VEGF-D (KidVD) alters adaptive immune cell populations and inflammatory progression. Preliminary data suggests increased renal lymphatic density primes the adaptive immune response and attenuates renal fibrosis. For the second aim, determining how a LEC specific deletion of S1P, a bioactive, alters renal immune cell clearance and the adaptive immune response in AKI may provide a novel renal targeted therapeutic option. To address how LECs regulate AKI associated inflammation and recovery a combination of lymphatic specific genetic models, renal injury models, and immune cell phenotyping will identify alterations in the renal immune cell response to AKI.