Long term effects of acute renal failure

急性肾衰竭的长期影响

• 批准号: 7884601
• 负责人: David P. Basile
• 金额: $ 36.31万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884601
• 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

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，与显著的死亡率相关。越来越多的人认识到，ARF使存活患者的肾脏易于发生长期并发症。我们先前已经发现ARF后肾小管周围毛细血管脱落的证据，并假设这是导致进行性肾脏疾病的一个重要因素。上一个项目期间的工作表明，从ARF恢复后，钠饮食易患高血压和加速慢性肾脏疾病。虽然血管脱落可能导致这种功能改变，但在本申请中还假设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改变，并确定氧化应激系统在肾血流动力学和钠排泄改变中的作用。这些研究将集中于缺血后对灌注压、血管紧张素II的反应，并确定VEGF的保护机制。第二个具体目标将直接探索血管脱落;研究将评估肾脏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的疗效，有和没有血管生成生长因子治疗。我们将比较来源于骨髓或血管壁的EPC，以确定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，并评估长期肾功能和CRF进展。最终特定目的（#3）旨在定义间质性肌成纤维细胞与血管脱落对ARF后进展为CRF的相对影响。这些研究将利用携带HSV胸苷激酶基因的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，与显著的死亡率相关。随着ARF存活患者数量的增加，人们逐渐认识到ARF易患继发性慢性肾脏疾病和高血压。本申请中的工作将利用发展为继发性慢性肾脏疾病的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。需要获得这一信息，以便为这一日益明显的健康问题制定有效的战略。