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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：
9976522
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976522
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（AKI）是诱发慢性肾脏疾病（CKD）的重要因素