Long term effects of acute renal failure

描述(由申请人提供)：急性肾功能衰竭(ARF)是最常见的需要住院治疗的肾脏疾病，并与显著的死亡率有关。越来越多的人认识到，ARF使存活患者的肾脏容易出现长期并发症。我们以前已经证明了ARF后肾小管周围毛细血管脱落的证据，并假设这是导致进展性肾脏疾病的一个重要因素。前一个项目期的工作表明，在ARF康复后，钠饮食易患高血压，并加速慢性肾脏疾病。虽然血管脱落可能导致这种功能的改变，但在目前的应用中，还假设I/R引起的血管反应性和成纤维细胞沉积的改变也可能有助于导致CRF的肾功能改变。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脏血流动力学和钠排泄变化中的作用。这些研究将集中在缺血后对灌流压力和血管紧张素II的反应，并确定血管内皮生长因子的保护机制。第二个具体目标将直接探讨血管脱落；该研究将评估内皮祖细胞在肾脏中的增殖潜力，并评估内皮祖细胞(EPC)在使用和不使用血管生成生长因子治疗的情况下在损伤后恢复肾血管功能方面的有效性。我们将比较来自骨髓和血管壁的EPC，确定EPC的来源是否影响长期的肾血管功能。研究将确定EPC细胞是否参与促进新血管的形成，在血管生成生长因子的影响下影响肾血流，并评估CRF的长期肾功能和进展。最终的具体目标(#3)旨在确定间质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胸苷激酶基因成纤维细胞特异性表达的转基因小鼠，在ARF诱导后耗尽(Myo)成纤维细胞。这些研究旨在区分间质细胞和肾小管周围毛细血管丢失在导致肾功能和血流动力学长期改变方面的影响。公共卫生背景急性肾功能衰竭(ARF)是最常见的肾脏疾病，需要住院治疗，并与显著的死亡率相关。随着存活于ARF的患者数量的增加，人们逐渐认识到ARF是继发性慢性肾脏疾病和高血压的易患因素。这项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的结构和功能，从而发展为慢性肾脏疾病。需要获得这些信息，以便为这一日益明显的健康问题设计有效的战略。

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.