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)是临床肾脏病的常见问题，并与重症监护环境中的高死亡率有关。此外，AKI越来越被认为是慢性肾脏疾病(CKD)进展的重要因素。使肾细胞适应急性和慢性缺氧的一个中心途径是pVHL/PHD/HIF途径。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，长时间的上皮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剖析特定细胞类型的HIF功能及其在调节肾脏代谢中的作用。在此，我们假设HIF诱导的肾脏代谢重编程在决定缺氧性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的体外模型来研究急性和慢性HIF激活在肾脏中的代谢后果。提出了四个具体目标。目的1研究PHD/HIF在缺血性AKI中的作用，AIM 2研究与急、慢性HIF激活相关的代谢变化，AIM 3研究代谢重编程在肾炎症和纤维化发展中的作用，AIM 4研究控制代谢的新HIF靶点的分子调控。 公共卫生相关性：这项拨款调查了VHL/HIF/PHD通路在肾脏代谢重新编程中的作用。这项建议的一个主要焦点是急性缺血性肾损伤和HIF激活的急性和慢性影响。在这项拨款下提出的工作将进一步加深我们对导致细胞保护的分子机制的理解，并有可能利用治疗手段来改善缺血性肾损伤患者的预后。

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. PUBLIC HEALTH RELEVANCE: This grant investigates the role of the VHL/HIF/PHD pathway in metabolic re- programming of the kidney. A major focus of this proposal is on acute ischemic kidney injury and the acute and chronic effects of HIF activation. Work proposed under this grant will further our understanding of molecular mechanism that leads to cytoprotection with the potential for therapeutic exploitation to improve the outcome of patients with ischemic kidney injuries.