Acute renal failure after whole body ischemia

描述（由申请方提供）：自体肾中的急性肾衰竭（ARF）与高死亡率和发病率相关。尽管在ARF的发病机制方面取得了重大进展，但没有特异性治疗方法。大多数关于缺血性ARF的实验工作使用孤立的肾损伤模型。然而，当患者在自体肾脏中发生缺血性ARF时，例如在休克或脓毒症期间，这几乎总是全身事件而不是孤立的肾脏事件的结果。全身缺血再灌注损伤（Whole body ischemia reperfusion injury，WBIRI）是一种独特的损伤状态，可同时累及肾脏和肺、心、肠等多个器官。鉴于目前缺乏针对ARF的特异性治疗，以及需要开发更接近人类疾病复杂性的更多“临床”模型，我们已经开始开发一种新的小鼠全身IRI动物模型，导致ARF。我们用氯化钾注射进行了WBIRI，由于心脏停止，导致血压完全丧失。心脏骤停后，小鼠进行心肺复苏。存活的动物均发生ARF。在初步研究中，我们发现血清肌酸酐升高，发生肾小管坏死，白细胞浸润到肾脏中。基于我们在这种新型ARF小鼠模型中的初步数据，我们建议更好地表征病理生理过程，如炎症，凋亡，氧化应激和腺嘌呤核苷酸。此外，我们将检查心脏，肺，肝脏和肠道的肾外功能变化，这些变化可能与WBIRI期间的肾损伤相互作用。第二个目的是直接比较WBIRI模型与经典的离体肾缺血模型中的肾脏病理生理过程。我们的长期目标是开发一个临床相关的实验模型，可用于开发新的治疗ARF。

DESCRIPTION (provided by applicant): Acute renal failure (ARF) in the native kidney is associated with a high mortality and morbidity. Despite major advances in the pathogenesis of ARF, there is no specific treatment. Most experimental work on ischemic ARF has used isolated renal injury models. However, when a patient develops ischemic ARF in the native kidney, such as during shock or sepsis, this is almost always a consequence of a whole body event rather than an isolated kidney event. Whole body ischemia reperfusion injury (WBIRI) creates a unique state that affects kidney and many organs simultaneously including lung, heart, intestine, etc. The global changes to the internal milieu are difficult to mimic in isolated organ models and in vitro preparations. In view of the current lack of specific therapy for ARF, as well as the need for the development of more "clinical" models that are closer to the complexity of human disease, we have started to develop a new animal model of whole body IRI in the mouse that leads to ARF. We have performed WBIRI with potassium chloride injection, which results in complete loss of blood pressure due to stoppage of the heart. After cardiac arrest, the mouse undergoes cardiopulmonary resuscitation. The surviving animals uniformly develop ARF. In preliminary studies, we have found that serum creatinine rises, tubular necrosis occurs, and leukocytes infiltrate into the kidney. Based on our preliminary data in this novel murine model of ARF, we propose to better characterize pathophysiologic processes such as inflammation, apoptosis, oxidative stress and adenine nucleotides. In addition, we will examine extra-renal functional changes in heart, lungs, liver and gut that likely interplay with kidney injury during WBIRI. The second aim will be to directly compare the renal pathophysiological processes in the WBIRI model with the classic isolated kidney ischemia model. Our long-term goals are to develop a clinically relevant experimental model which can be used to develop novel therapies for ARF.