Long-term effects of acute renal failure

描述（由申请人提供）：急性肾衰竭被认为是很大程度上可逆的，如果患者在最初的损害中幸存下来。急性肾功能衰竭恢复后的患者可能易患进行性肾脏疾病，尽管这种情况并不常见。相比之下，移植肾的缺血性损伤可导致移植物功能延迟（DGF），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行性肾病之间关系的本质，我们对单侧或双侧缺血/再灌注损伤后恢复的大鼠进行了研究，结果表明肾小管毛细血管结构发生了永久性改变。我们假设肾小管毛细血管的减少会改变肾功能并导致慢性肾脏疾病的发生。该应用旨在阐明急性损伤的生理和病理生理意义，并破译急性损伤后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。在这个目的中，我们将使用BOLD MRI研究肾脏pO2的改变。此外，我们将确定肾毒性（如环孢素）损伤是否会以与I/R损伤相似的方式影响肾小管毛细血管。我们还将确定缺血恢复后的动物的肾钠处理能力是否受到影响，并发展为盐敏感性高血压。我们还将确定潜在的介入治疗（ACE/、VEGF）是否会影响I/R诱导的肾毛细血管密度、肾缺氧和/或慢性肾脏疾病的进展。最后，我们将分析恢复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。在具体目标#2中，我们将进行旨在了解损伤后血管丢失机制的实验。在这个目的中，我们将描述几种血管生成和抗血管生成分子在I/R损伤反应中的表达。该目标的第二个方面是利用不同的敲除小鼠品系或新获得的金属蛋白酶抑制剂来解读血管抑制素的作用和调控。

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.