Long-term effects of acute renal failure

急性肾衰竭的长期影响

• 批准号: 6878804
• 负责人: David P. Basile
• 金额: $ 2.73万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 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 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878804
• 关键词: ACE inhibitors; acute renal failure; angiogenesis inhibitors; angiostatins; capillary bed; chronic renal failure; disease /disorder proneness /risk; gene expression; gene targeting; genetically modified animals; hypertension; injury /disease stressor; kidney circulation; kidney disorder chemotherapy; kidney function; laboratory mouse; laboratory rat; nonhuman therapy evaluation; oxygen tension; protease inhibitor; renal ischemia /hypoxia; renal toxin; saluresis; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Acute renal failure is thought to be largely reversible if the patient survives the initial insult. Patients following recovery from ARF may be susceptable to progressive renal disease, although this is not commonly observed. In contrast, ischemic injury in a transplanted kidney can result in delayed graft function (DGF) which is a clearly a risk factor for long-term graft demise. To understand more clearly the nature of the relationship between acute renal injuries and progressive nephropathies, we have studied rats following recovery from either unilateral or bilateral ischemia/reperfusion injury and showed that there is a permanent alteration in the structure of renal per/tubular capillaries. We hypothesize that a reduction in renal per/tubular capillaries alters renal function and predisposes the development of chronic renal disease. This application is directed toward elucidating the physiological and pathophysiological implications of acute injuries and to decipher possible mechanims by which renal per/tubular capillaries are lost following acute insults. In specific aim #1, we will explore further the ramification of acute injury on long-term renal function. In this aim, we will investigate alterations in renal pO2 using BOLD MRI. In addition, we will determine if nephrotoxic (e.g., cyclosporine) injury can affect per/tubular capillaries in a fashion similar to that observed with I/R injury. We will also determine if post-ischemic recovered animals have are affected in their renal Na handling abilities and develop salt-sensitive hypertension. We will also determine whether potential intervential therapies (ACE/, VEGF) affect I/R induced changes in renal capillary density, renal hypoxia and/or the progression of chronic renal disease. Finally, we will analyze gene expression patterns in recovered kidneys to gain insight into the potential mechanisms of chronic renal failure following acute injury. In Specific Aim #2, we will perform experiments geared toward understanding the mechanims of blood vessel loss following injury. In this aim, we will characterize the expression of several angiogenic and antiangiogenic molecules in response to I/R injury. The second aspect of this aim is geared toward deciphering the role and regulation of angiostatin using different strains of knockout mice or newly acquired metalloprotease inhibitors.

描述(申请人提供)：急性肾功能衰竭被认为在很大程度上是可逆的，如果患者在最初的侮辱中存活下来的话。ARF恢复后的患者可能易患进展性肾脏疾病，尽管这种情况并不常见。相反，移植肾的缺血损伤会导致移植物功能延迟，这显然是移植物长期死亡的一个危险因素。为了更清楚地了解急性肾损伤与进展性肾病之间关系的本质，我们研究了单侧或双侧缺血/再灌注损伤后的大鼠，发现肾小管/肾小管毛细血管结构发生了永久性的变化。我们假设，肾小管/肾小管毛细血管减少会改变肾功能，并易导致慢性肾脏疾病的发生。这项应用旨在阐明急性损伤的生理学和病理生理学意义，并破译急性损伤后肾小管/肾小管毛细血管丢失的可能机制。在具体目标1中，我们将进一步探讨急性损伤对长期肾功能的影响。在这个目标中，我们将使用BOLD MRI来研究肾脏PO2的变化。此外，我们将确定肾毒性(例如，环孢素)损伤是否会以类似于I/R损伤的方式影响PER/小管毛细血管。我们还将确定缺血后恢复的动物是否会受到肾脏钠处理能力的影响，并发展成盐敏感型高血压。我们还将确定潜在的介入治疗(ACE/、血管内皮生长因子)是否影响I/R引起的肾脏毛细血管密度的变化、肾脏缺氧和/或慢性肾脏疾病的进展。最后，我们将分析恢复的肾脏的基因表达模式，以深入了解急性损伤后慢性肾功能衰竭的潜在机制。在特定的目标#2中，我们将进行实验，旨在了解损伤后血管丢失的机制。在这一目标中，我们将表征几种血管生成和抗血管生成分子在I/R损伤中的表达。这一目标的第二个方面是利用不同品系的基因敲除小鼠或新获得的金属蛋白酶抑制剂来破译血管抑素的作用和调节。