Molecular Mechanisms of Renal Injury

描述（由申请人提供）：由缺血再灌注损伤引起的急性肾损伤（AKI）是临床肾脏病学中的一个常见问题，并与重症监护环境中的高死亡率相关。此外，AKI越来越被认为是慢性肾脏疾病（CKD）进展的重要因素。pVHL/PHD/HIF通路是肾细胞适应急性和慢性缺氧的中心通路。我们的实验室和其他研究小组已经证明，短期激活HIF在预防急性缺血性损伤及其长期后遗症方面具有巨大的治疗潜力。另一方面，延长上皮HIF激活会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解剖细胞类型特异性HIF功能及其在肾脏代谢调节中的作用。在这里，我们假设hif诱导的肾脏代谢重编程在决定低氧肾损伤的生物学结果中起着核心作用。在这项资助下，我们使用基因工程小鼠和AKI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AKI中的作用，目的2研究与急性和慢性HIF激活相关的代谢变化，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.