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Long-term effects of acute renal failure

急性肾衰竭的长期影响

基本信息

批准号：
10218139
负责人：
David P. Basile
金额：
$ 48.98万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218139
关键词：
Acute Kidney Failure Acute Renal Failure with Renal Papillary Necrosis Animal Model Antibodies Attention Attenuated Autoimmune Diseases Biochemical Biological Markers Blood Blood Pressure Blood Vessels Blood capillaries CD4 Positive T Lymphocytes Calcium Signaling Cardiovascular Diseases Caring Cells Chronic Kidney Failure Clinical Communities Data Development Diagnosis Disease Progression Distant End stage renal failure Epithelial Cells Excretory function Exposure to Fibrosis Functional disorder Generations Genes Goals Hospitalization Hospitals Human Hypertension IL17 gene Immune Impairment In Vitro Incidence Infiltration Inflammation Inflammatory Inflammatory Bowel Diseases Injury to Kidney Interleukin-17 Kidney Kidney Diseases Knock-out Laboratories Long-Term Effects Lupus Lymphocyte Measures Mediating Mediation Mediator of activation protein Messenger RNA Modeling Multiple Sclerosis Mutate Nephrology Outcome Oxidative Stress Pathologic Pathway interactions Patients Pericytes Peripheral Physiological Plasma Play Population Predisposing Factor Process Production Psoriasis Rattus Reactive Oxygen Species Recovery Renal function Reperfusion Injury Residual state Resolution Risk Risk Factors Role Sampling Series Signal Pathway Signal Transduction Sodium Stimulus Survivors T-Lymphocyte Testing Therapeutic Time Transgenic Organisms Translating Work animal data base cytokine density design dietary salt epithelium regeneration extracellular follow-up high salt diet in vitro Assay in vivo interstitial kidney fibrosis mortality novel organ injury patient population programs response salt sensitive hypertension transdifferentiation

项目摘要

Acute kidney injury (AKI) is a significant factor predisposing chronic kidney disease (CKD), however the factors mediating CKD progression are not clear. Work from the previous project period identified T-helper 17 cells (Th-17) as a primary lymphocyte population activated by AKI and further demonstrated that it is strongly activated by exposure of post AKI rats to high salt diet. Recent preliminary data indicate a potential role for altered lymphocyte intracellular calcium signaling in mediating enhanced IL17 activity. The overarching hypothesis to be tested is that AKI results in persistent IL-17 activity from CD4+ cells and this activity is integral to the subsequent development of CKD. As such, Specific aim 1 of this application will investigate the role of Th-17 cells in the mediation of the AKI to CKD transition in rats. The studies will utilize a rat model of AKI-to CKD established in our laboratory. Two approaches will be used to inhibit Th17 activity. In one series of studies, we will use an antibody-based approach to block IL17 activity in rats in vivo. Additional studies will utilize a transgenic rat in which the RORᵞT gene has been mutated. This rat shows impaired activation of Th-17 cells following AKI and lymphocytes obtained from these rats show an impaired IL17 responses in vitro. Using either approach we will test whether Th17 cells activated by elevated dietary salt following recovery from AKI participate in the processes of renal fibrosis, sodium sensitive hypertension, altered vascular reactivity and distant organ injury following AKI Specific aim 2 of this application will more precisely examine altered lymphocyte signaling associated with IL17. Isolated lymphocytes from normal or post AKI rats will be stimulated in vitro (by elevated Na+ and Ang II) for enhanced IL17 synthesis. The goal of these studies will be to determine how prolonged enhanced IL17 responses to are retained in CD4 cells following resolution of renal injury. We will also investigate potential physiologically relevant mediators that may activate these responses in vivo. Additional studies in this aim will investigate contribution of the store-operated Ca++ Oria1 to altered Ca signaling and the IL17 response. Finally studies in this aim will seek to investigate the effect of in vivo inhibition of Oria-1 on the activation of Th-17 cells and the AKI to CKD transition. Specific aim 3 will determine whether activation of Th17 cells may underlie the AKI to CKD transition in human patients. These studies will utilize samples available from the ASSESS-AKI consortium which has collected samples from AKI patients for up to 4 years following hospital discharge. We will compare circulating Th17 cytokines as an initial step to determine the activity of this pathway in patients with AKI who progress versus patients who recovery renal function as well as control patients.

急性肾损伤（阿基）是诱发慢性肾病（CKD）的重要因素，然而，目前尚不清楚CKD进展的介导因素。上一个项目期间的工作确定了T辅助细胞17 （Th-17）作为由阿基激活的初级淋巴细胞群体，并进一步证明其强烈地抑制AKI的免疫应答。阿基后大鼠暴露于高盐饮食激活。最近的初步数据表明，在介导增强的IL 17活性中改变淋巴细胞细胞内钙信号传导。总体待检验的假设是阿基导致来自CD 4+细胞的持续IL-17活性，活动是CKD后续发展的组成部分。具体目标1 本申请将研究Th-17细胞在大鼠中阿基向CKD转变的介导中的作用。的研究将利用我们实验室建立的AKI-CKD大鼠模型。将采用两种方法，抑制Th 17活性。在一系列研究中，我们将使用基于抗体的方法来阻断IL 17活性，大鼠体内。进一步的研究将利用转基因大鼠，其中ROR β T基因已发生突变。这只老鼠显示阿基后Th-17细胞活化受损，从这些大鼠获得的淋巴细胞显示AKI后Th-17细胞活化受损。体外IL 17应答受损。使用这两种方法，我们将测试Th 17细胞是否被升高的从阿基恢复后的膳食盐参与肾纤维化、钠敏感性、高钠血症和高钠血症的过程。阿基后高血压、血管反应性改变和远端器官损伤本申请将更精确地检测与IL 17相关的改变的淋巴细胞信号传导。分离将在体外刺激来自正常或阿基后大鼠的淋巴细胞（通过升高的Na+和Ang II），以增强 IL 17合成。这些研究的目的是确定IL-17应答增强的时间有多长。在肾损伤消退后保留在CD 4细胞中。我们还将研究潜在的生理学可能激活这些反应在体内的相关介质。在这个目标的进一步研究将调查钙库操纵的Ca++ Oria 1对改变的Ca信号传导和IL 17应答的贡献。最后研究在该目的将寻求研究体内抑制奥里亚-1对Th-17细胞活化的影响，阿基向CKD过渡。具体目标3将确定Th 17细胞的活化是否可能是阿基的基础，人类患者中的CKD转变。这些研究将利用ASSESS-AKI提供的样本该联盟已经从阿基患者出院后收集了长达4年的样本。我们将比较循环Th 17细胞因子作为确定患者中该途径活性的初始步骤阿基进展患者与肾功能恢复患者以及对照患者的比较。