Lymphatics and lymphangiogenesis in kidney function and inflammation

肾功能和炎症中的淋巴管和淋巴管生成

• 批准号: 10507856
• 负责人: Joseph Michael Rutkowski
• 金额: $ 5.3万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-23 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10507856
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; American; Antigens; Bilateral; Biological Markers; Biological Models; Biology; Cells; Characteristics; Chronic; Chronic Kidney Failure; Cisplatin; Clinical; Closure by clamp; Data; Diabetes Mellitus; Disease; Disease Progression; Epidemic; Excretory function; Exhibits; Fibrosis; Functional disorder; Future; Genetic; Genetic Models; Genetic Techniques; Goals; Health; Healthcare; Homeostasis; Human; Hypertension; Immune; Immune response; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Ischemia; Kidney; Kidney Diseases; Knowledge; Liquid substance; Lymphangiogenesis; Lymphatic; Medicare; Metabolism; Minerals; Mission; Modeling; Molecular Genetics; Morbidity - disease rate; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Osteoporosis; Outcome; Pathogenesis; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Physiological; Physiology; Positioning Attribute; Pre-Clinical Model; Prognosis; Proteinuria; Public Health; Publishing; Regulation; Renal function; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Resistance; Risk; Risk Factors; Role; Route; Severities; Sodium; Testing; Therapeutic; Tissues; United States National Institutes of Health; Up-Regulation; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-3; Work; animal data; chronic inflammatory disease; cytokine; density; high salt diet; improved; injury recovery; innovation; inorganic phosphate; interstitial; kidney preservation; lymphatic vasculature; lymphatic vessel; macromolecule; mortality; mouse model; nephrotoxicity; novel; overexpression; pressure; prevent; response; response to injury; sodium phosphate; solute; statistics; success; tissue injury

PROJECT SUMMARY Acute kidney injury (AKI) is a major cause of patient morbidity and mortality and appears to be a substantial risk factor for future progression to chronic kidney disease (CKD). According to NIDDK statistics, roughly 14% of Americans exhibit indications of CKD and 20% of all Medicare spending goes towards it management. Slowing AKI-to-CKD progression, or identifying those patients most at risk for future CKD following AKI, is currently not possible largely due to a fundamental gap in understanding of the pathogenesis of AKI-to-CKD transition. Inflammation-associated lymphangiogenesis (LAG) is critical in regulating inflammation through fluid, macromolecule (cytokines and antigens), and immune cell transport. While LAG has been identified in a host of kidney diseases, reports have been mostly correlative. The long-term goal is to identify the mechanisms by which lymphatics regulate tissue biology in chronic inflammatory disease. The overall objective in this application is to identify the roles of the renal lymphatic vasculature during kidney injury and exploit the induction of enhanced LAG as a potential therapy. The central hypothesis is that increasing renal lymphatics provides a route of immune cell clearance while also potentially regulating solute transport. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine how renal LAG affects inflammation and renal function in AKI; and 2) Determine the mechanisms by which renal LAG reduces AKI-to- CKD progression; and 3) Determine the impact of enhancing renal lymphatic density on CKD. Under the first aim, 3 models of AKI with diverse pathophysiologies will be used to identify how lymphatic density changes with AKI and whether expanding lymphatics using KidVD mice, a genetic model of kidney-specific LAG, can limit the AKI inflammatory response. Preliminary data suggest increased LAG protects against AKI. In the second aim, how LAG alters the progression of AKI-to-CKD will be determined. Additionally, how changes in interstitial pressures and mineral metabolism in the kidney with increased LAG during sodium and phosphate challenge may provide a novel mechanism for AKI protection. For the third aim, therapeutic strategies to induce LAG once CKD is established will be tested in each of the 3 renal pathologies. The proposed research is innovative, in the applicant’s opinion, because it addresses and specifically targets the lymphatic vasculature of the kidney to improve kidney function and inflammation upon AKI. New potential therapies and biomarkers are expected to result from this work. The proposed research is significant because it is expected to identify previously unknown mechanisms of kidney inflammatory regulation and transport functions. Ultimately, understanding the mechanisms by which lymphatic vessels regulate kidney function and health has the potential to be transformative to AKI response and treatment and in remediating the current epidemic of incurable chronic kidney disease.

项目摘要 急性肾脏损伤（AKI）是患者发病率和死亡率的主要原因，似乎是一个很大的风险 未来发展为慢性肾脏疾病（CKD）的因素。根据NIDDK统计，约有14％ 美国人表现出CKD的迹象，所有医疗保险支出中有20％用于IT管理。放缓 AKI到CKD的进展，或者在AKI之后识别那些最有可能将来CKD的患者，目前尚未 可能很大程度上是由于理解AKI到CKD转变的发病机理的根本差距。 炎症相关的淋巴管生成（滞后）对于通过液体调节注射至关重要， 大分子（细胞因子和抗原）和免疫核管转运。尽管滞后已在许多人中识别 肾脏疾病，报告主要相关。长期目标是通过 哪些淋巴管调节慢性炎症性疾病中的组织生物学。总体目标 应用是确定肾脏损伤期间肾脏淋巴管的作用并利用诱导 增强的滞后作为潜在疗法。中心假设是增加肾脏淋巴管提供了 免疫细胞清除途径，同时也有可能控制固体转运。在强大的初步指导下 数据，该假设将通过追求三个具体目标来检验：1）确定肾滞后如何影响 AKI的炎症和肾功能； 2）确定肾脏滞后降低Aki至 - 到 - 的机制 CKD进展； 3）确定增强肾淋巴密度对CKD的影响。在第一个 目的，将使用3种具有潜水病理生理学的AKI模型来确定淋巴密度如何随着 AKI以及使用KIDVD小鼠（一种肾脏特异性滞后的遗传模型）扩展淋巴机可以限制 AKI炎症反应。初步数据表明，增加的滞后可以预防AKI。在第二个目标中 将如何确定滞后如何改变Aki-to-CKD的进展。此外，间隙的变化如何 肾脏的压力和矿物质代谢，钠和磷酸盐挑战期间滞后增加 可以为AKI保护提供一种新颖的机制。对于第三个目的，诱导滞后的治疗策略 建立CKD将在3种肾脏病理中的每一种中进行测试。拟议的研究是创新的，在 申请人的意见，因为它针对并专门针对肾脏的淋巴脉管系统 改善AKI的肾功能和炎症。预计新的潜在疗法和生物标志物将 这项工作的结果。拟议的研究很重要，因为它有望识别以前未知的 肾脏炎症调节和运输功能的机制。最终，理解 淋巴管调节肾功能和健康的机制有可能 对AKI反应和治疗的变革性，并修复当前无法治愈的慢性流行病 肾脏疾病。