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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：
8636448
负责人：
David P. Basile
金额：
$ 33.93万
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 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8636448
关键词：
Activated Lymphocyte Acute Kidney Failure Acute Renal Failure with Renal Papillary Necrosis Adoptive Transfer Antigen-Presenting Cells Antihypertensive Agents Attenuated Biological Preservation Blood Vessels Blood capillaries CCR CD27 Antigens Cardiovascular system Cell Differentiation process Cells Chronic Chronic Kidney Failure Contralateral Data Deposition Development Diet Dietary Sodium Disease Pathway Dropout End stage renal failure Evaluation Excretory function Fibrosis Healthcare Hospitalization Hypertension Hypoxia Immune Immune response Immunosuppression Immunosuppressive Agents Incidence Inflammatory Injury Ischemia Kidney Kidney Diseases Laboratories Left Link Long-Term Effects Lymphocyte Lymphocyte Suppression Lymphocyte antigen Mediating Modeling Nature North America Pathway interactions Patients Physiological Predisposing Factor Process Production Published Comment Publishing Rattus Recovery Reducing diet Regulation Regulatory T-Lymphocyte Renal Mass Renal Tissue Renal function Reperfusion Injury Reperfusion Therapy Residual state Risk Secondary to Sepsis Sodium Chloride Source Staging Structure T cell differentiation T-Lymphocyte TNFSF5 gene Testing Tissues Toxic effect Tubular formation Work base blood pressure regulation capillary chemokine cytokine density hemodynamics immune function injured mortality mycophenolate mofetil novel oxidant stress programs public health relevance receptor renal ischemia repaired response salt sensitive salt sensitive hypertension synergism tissue repair

项目摘要

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a significant factor predisposing chronic kidney disease (CKD), however the nature of the relationship is not clear. We demonstrated that renal capillary density is permanently compromised in rats following AKI induced by ischemia reperfusion (I/R). AKI alters renal hemodynamic responses and predisposes to salt- sensitive hypertension and we demonstrated that preservation of vascular structure following I/R attenuates high-salt induced CKD. However, immunosuppression also blocked salt-induced hypertension and CKD following AKI. Moreover, preliminary studies on the contralateral kidney following unilateral AKI (termed "remote/indirect" AKI) demonstrates that circulating factors alter hemodynamic function in the absence of direct injury. Our overarching hypothesis is that AKI alters chronic renal function due to vascular dropout and activation and differentiation of T lymphocytes, which have independent and synergistic effects to promote hypertension and CKD. Rats will be studied in models of "direct AKI" injury and "remote AKI" in combination with reduced renal mass and high salt diet. Specific aim 1 will test the hypothesis that AKI promotes the persistent deposition of T cells and their cytokine profiles are modulated by the type of injury (direct vs. remote), reduced renal mass, and dietary salt. These studies will utilize FACS analysis and characterize T helper differentiation by assessing cytokine profiles produced by T-cells, and the activation of antigen presenting cells following injury. Specific aim 2 will test the hypothesis that AKI primed lymphocytes influence renal hemodynamic function, hypertension and CKD following direct or remote renal injury. These studies will utilize both immunosuppressive and adoptive transfer approaches to evaluate alterations in hemodynamic control. Additional studies using adoptive transfer into injured or non-injured T cell deficient ras will be used to evaluate the distinct and synergistic interactions of AKI and injury activated T cells on salt induced CKD. Finally, Specific aim 3 will evaluate the hypothesis that T cell differentiation induced by high salt diet (following direct injury), is a key step in the AKI to CK transition. These studies will use strategies to block specific co-stimulatory and chemokine pathways which may specifically enhanced T cell differentiation and determine if commonly utilized anti-hypertensive treatments influence T-cell differentiation in response to high salt die following AKI.

描述（由申请方提供）：急性肾损伤（阿基）是诱发慢性肾病（CKD）的重要因素，但其关系的性质尚不清楚。我们证明，肾毛细血管密度是永久性的损害，在大鼠急性肾损伤诱导缺血再灌注（I/R）。阿基改变肾脏血流动力学反应，易患盐敏感性高血压，我们证明I/R后血管结构的保护可减轻高盐诱导的CKD。然而，免疫抑制也阻断了盐诱导的高血压和阿基后的CKD。此外，对单侧阿基（称为“远程/间接”阿基）后对侧肾脏的初步研究表明，在没有直接损伤的情况下，循环因素会改变血流动力学功能。我们的总体假设是，阿基由于血管脱落以及T淋巴细胞的活化和分化而改变慢性肾功能，这对促进高血压和CKD具有独立和协同作用。将在“直接阿基”损伤和“远程阿基”模型中结合肾质量减少和高盐饮食对大鼠进行研究。具体目标1将检验以下假设：阿基促进T细胞的持续沉积，并且其细胞因子谱受损伤类型（直接与远程）、肾质量减少和饮食盐的调节。这些研究将利用FACS分析，通过评估T细胞产生的细胞因子谱和损伤后抗原呈递细胞的活化来表征T辅助细胞分化。具体目标2将检验以下假设：阿基致敏淋巴细胞影响直接或远程肾损伤后的肾血流动力学功能、高血压和CKD。这些研究将利用免疫抑制和过继转移方法来评价血流动力学控制的改变。将使用过继转移至损伤或非损伤T细胞缺陷型ras的其他研究来评价阿基和损伤活化T细胞对盐诱导的CKD的独特和协同相互作用。最后，具体目标3将评估高盐饮食诱导的T细胞分化（直接损伤后）是阿基向CK转变的关键步骤的假设。这些研究将使用策略来阻断特定的共刺激和趋化因子途径，这些途径可能专门增强T细胞分化，并确定常用的抗高血压治疗是否会影响T细胞分化以应对阿基后的高盐死亡。