权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Long term effects of acute renal failure

急性肾衰竭的长期影响

基本信息

批准号：
7920649
负责人：
David P. Basile
金额：
$ 8.62万
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：
2009
资助国家：
美国
起止时间：
2009-09-21 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7920649
关键词：
Acute Acute Kidney Failure Adult Affect Angiotensin II Blood Vessels Blood capillaries Bone Marrow Cells Childhood Chronic Chronic Kidney Failure Deposition Development Diet Disease Progression Dropout Elements Etiology Excretory function Fibroblasts Future Goals Growth Factor Health Hospitalization Human Hypertension Incidence Injury Injury to Kidney Ischemia Kidney Kidney Diseases Laboratories Lead Long-Term Effects Modeling Morphology Myofibroblast Nature Organ failure Oxygen Pathway interactions Patients Perfusion Population Predisposing Factor Predisposition Process Published Comment Rattus Recovery Relative (related person)Renal Blood Flow Renal function Reperfusion Injury Reperfusion Therapy Reporting Research Research Design Rodent Model Role Secondary to Simplexvirus Sodium Source Stem cells Structure Syndrome System TK Gene Transgenic Mice Transplantation Tubular formation Vascular Endothelial Growth Factors Vascular blood supply Work capillary delayed graft function density design hemodynamics interstitial interstitial cell kidney vascular structure mortality oxidant stress pressure public health relevance regenerative renal ischemia response restoration

项目摘要

DESCRIPTION (provided by applicant): Acute renal failure (ARF) is the most common renal disease requiring hospitalization and is associated with significant mortality. It is increasingly recognized that ARF predisposes the kidney to long-term complications in surviving patients. We have previously shown evidence for peritubular capillary dropout following ARF and hypothesized that this is an important factor predisposing progressive renal disease. Work from the previous project period has shown that following recovery from ARF, Na-diet predisposes hypertension and hastens chronic kidney disease. While vascular dropout may contribute to this alteration in function, it is additionally hypothesized, in the current application that I/R-induced alterations in vascular reactivity and fibroblast deposition may also contribute to alterations in renal function leading to CRF. Specific aim 1 will evaluate alterations in vascular reactivity and define the role of oxidant stress systems in the alterations of renal hemodynamics and sodium excretion. These studies will focus on the post-ischemic response to perfusion pressure, angiotensin II and determine the mechanism of protection by VEGF. The second specific aim will explore vascular dropout directly; the studies will evaluate the proliferative potential of endothelial progenitor cells in the kidney and evaluate the efficacy of endothelial progenitor cells (EPC) in restoring renal vascular function following injury, with and without angiogenic growth factor therapy. We will compare EPCs derived from either bone-marrow or from vessel walls, determine if the source of EPC affects long-term renal vascular function. Studies will determine if EPC cells incorporate to promote new blood vessel formation, affect renal blood flow under the influence of angiogenic growth factors, and evaluate long-term renal function and progression of CRF. The final specific aim (#3) is designed to define the relative impact of interstitial myofibroblast vs. blood vessel dropout on progression to CRF following ARF. These studies will utilize transgenic mice harboring fibroblast specific expression of the HSV thymidine kinase gene, to deplete (myo) fibroblasts following the induction of ARF. These studies are designed to separate the influence of interstitial cells vs. peritubular capillary loss in predisposing long term changes in renal function and hemodynamics. PUBLIC HEALTH RELEVANCE Acute renal failure (ARF) is the most common renal disease requiring hospitalization is associated with significant mortality. As the number of patients that survive ARF is increasing, it is becoming recognized that ARF predisposes secondary chronic kidney disease and hypertension. The work in this application will utilize rodent models of ARF that develop secondary chronic kidney disease. The overall goal is to gain an understanding as to how acute injury changes kidney structure and function so as to develop into chronic kidney disease. The acquisition of this information is required to design effective strategies for this increasingly apparent health problem.

描述（由申请人提供）：急性肾衰竭（ARF）是最常见的需要住院治疗的肾脏疾病，并且与显着的死亡率相关。人们越来越认识到，ARF 会使存活患者的肾脏容易出现长期并发症。我们之前已经证明了 ARF 后管周毛细血管脱落的证据，并假设这是诱发进行性肾病的重要因素。上一个项目期间的工作表明，从 ARF 恢复后，钠饮食会诱发高血压并加速慢性肾脏病。虽然血管脱落可能导致这种功能改变，但在目前的应用中还假设I/R诱导的血管反应性和成纤维细胞沉积的改变也可能导致肾功能改变，导致CRF。具体目标 1 将评估血管反应性的变化，并确定氧化应激系统在肾血流动力学和钠排泄变化中的作用。这些研究将重点关注缺血后对灌注压、血管紧张素 II 的反应，并确定 VEGF 的保护机制。第二个具体目标是直接探索血管脱落；这些研究将评估肾脏中内皮祖细胞的增殖潜力，并评估内皮祖细胞（EPC）在损伤后恢复肾血管功能（无论有无血管生成生长因子治疗）方面的功效。我们将比较源自骨髓或血管壁的 EPC，确定 EPC 的来源是否影响长期肾血管功能。研究将确定 EPC 细胞是否参与促进新血管形成、在血管生成生长因子的影响下影响肾血流量，并评估长期肾功能和 CRF 的进展。最终的具体目标 (#3) 旨在定义间质肌成纤维细胞与血管脱落对 ARF 后发展为 CRF 的相对影响。这些研究将利用携带 HSV 胸苷激酶基因成纤维细胞特异性表达的转基因小鼠，在诱导 ARF 后消耗（肌）成纤维细胞。这些研究旨在区分间质细胞与肾小管周围毛细血管损失对肾功能和血流动力学长期变化的影响。公共卫生相关性急性肾衰竭 (ARF) 是最常见的需要住院治疗的肾脏疾病，与显着的死亡率相关。随着 ARF 存活的患者数量不断增加，人们逐渐认识到 ARF 易诱发继发性慢性肾脏病和高血压。本申请的工作将利用发展继发性慢性肾病的 ARF 啮齿动物模型。总体目标是了解急性损伤如何改变肾脏结构和功能，从而发展为慢性肾脏疾病。需要获取这些信息来针对这一日益明显的健康问题设计有效的策略。