Molecular Mechanisms of Renal Injury

描述（由申请人提供）：缺血-再灌注损伤导致的急性肾损伤（阿基）是临床肾脏病学中的常见问题，与重症监护环境中的高死亡率相关。此外，阿基越来越被认为是慢性肾病（CKD）进展的重要因素。允许肾细胞适应急性和慢性缺氧的中心途径是pVHL/PHD/HIF途径。我们的实验室和其他小组已经证明，短期HIF激活对预防急性缺血性损伤及其长期后遗症具有巨大的治疗潜力。另一方面，延长的上皮HIF活化导致肾脏炎症和纤维化。为了了解细胞保护的分子和细胞基础，我们已经开始使用遗传学和药理学方法来剖析细胞类型特异性HIF功能及其在肾脏代谢调节中的作用。在此，我们假设HIF诱导的肾代谢重编程在决定缺氧性肾损伤的生物学结果中起着重要作用。在这项资助下，我们使用基因工程小鼠和阿基体外模型来研究肾脏中急性和慢性HIF激活的代谢后果。提出了四个具体目标。目的1研究上皮PHD/HIF在缺血性阿基中的作用，目的2研究与急性和慢性HIF活化相关的代谢变化，目的3研究代谢重编程在肾脏炎症和纤维化发展中的作用，目的4研究控制代谢的新型HIF靶点的分子调控。

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) resulting from ischemia-reperfusion injury represents a common problem in clinical nephrology and is associated with high mortality in the critical care setting. Furthermore, AKI is increasingly recognized as an important contributor to the progression of chronic kidney disease (CKD). A central pathway that allows renal cells to adapt to acute and chronic hypoxia is the pVHL/PHD/HIF pathway. Our laboratory and other groups have demonstrated that short-term HIF activation has great therapeutic potential for the prevention of acute ischemic injuries and their long-term sequelae. Prolonged epithelial HIF activation on the other hand results in renal inflammation and fibrosis. To understand the molecular and cellular basis of cytoprotection, we have begun to use genetic and pharmacologic approaches to dissect cell type-specific HIF functions and their role in the regulation of renal metabolism. Here we hypothesize that HIF-induced re- programming of renal metabolism plays a central role in determining the biological outcome of hypoxic kidney injuries. Under this grant we use genetically engineered mice and in vitro models of AKI to investigate the metabolic consequences of acute and chronic HIF activation in the kidney. Four specific aims are proposed. Aim 1 investigates the role epithelial PHD/HIF in ischemic AKI, aim 2 examines the metabolic changes that associate with acute and chronic HIF activation, aim 3 investigates the role of metabolic re-programming in the development of renal inflammation and fibrosis, and aim 4 investigates the molecular regulation of novel HIF targets that control metabolism.