Long-term effects of acute renal failure

描述（由申请人提供）：如果患者在初始损伤后存活，则认为急性肾衰竭在很大程度上是可逆的。ARF恢复后的患者可能易发生进行性肾脏疾病，尽管这并不常见。相比之下，移植肾中的缺血性损伤可导致移植物功能延迟（DGF），这显然是长期移植物死亡的危险因素。 为了更清楚地了解急性肾损伤和进行性肾病之间的关系的性质，我们研究了单侧或双侧缺血/再灌注损伤恢复后的大鼠，并表明肾小管毛细血管结构存在永久性改变。我们假设肾毛细血管/肾小管毛细血管的减少改变了肾功能，并易患慢性肾脏疾病。本申请旨在阐明急性损伤的生理学和病理生理学意义，并解释急性损伤后肾/肾小管毛细血管丢失的可能机制。在具体目标1中，我们将进一步探索急性损伤对长期肾功能的影响。为此，我们将使用BOLD MRI研究肾脏pO 2的变化。此外，我们将确定是否有肾毒性（例如，环孢霉素）损伤可以以与I/R损伤所观察到的相似的方式影响每/肾小管毛细血管。我们还将确定缺血后恢复的动物的肾钠处理能力是否受到影响并发展成盐敏感性高血压。我们还将确定潜在的介入治疗（ACE/VEGF）是否影响I/R诱导的肾毛细血管密度变化、肾缺氧和/或慢性肾脏疾病进展。 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损失机制的实验。在这一目标中，我们将表征的表达的几个血管生成和抗血管生成分子在响应I/R损伤。这个目标的第二个方面是面向破译的作用和调节血管抑素使用不同品系的敲除小鼠或新获得的金属蛋白酶抑制剂。

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.