Mechanisms of differential function of HIF-1 and HIF-2 in human renal tubular cells

尽管肾脏的血液供应量很高，但肾脏中肾小管系统的特定部分特别容易受到缺氧损伤。在细胞中，缺氧导致缺氧诱导转录因子（HIF）的稳定，其激活转录级联以促进细胞完整性和存活。在实验模型中，肾小管细胞中HIF系统的预条件激活导致缺血性或毒性损伤后更好的器官功能。此外，HIF系统也在与von Hippel-Lindau蛋白缺乏相关的肾细胞癌的发病机制中起关键作用。然而，目前尚不清楚哪些特定的基因和途径参与器官保护或细胞去分化，以及在动物模型中观察到的效应是否与人类相关。因此，本项目旨在调节原代人肾小管细胞和肾脏中的HIF系统，并彻底分析全基因组转录HIF反应。使用现代高通量测序技术，HIF DNA结合位点，突出的调控DNA元件和转录调控的变化将在人类中进行分析，并与其他物种中的保守遗传元件相关。由于HIF系统原则上可以通过阻断HIF脯氨酰羟化酶β 2来诱导，因此这些研究对急性或慢性肾衰竭的治疗具有重要意义。

Specific segments of the tubular system in the kidney are especially prone to hypoxic injuries, although the kidney has a high blood supply. In cells, hypoxia leads to stabilization of hypoxia-inducible transcription factors (HIF) which activate a transcriptional cascade to promote cell integrity and survival. In experimental models, the pre-conditional activation of the HIF-system in renal tubular cells leads to a better organ function after ischemic or toxic injuries. In addition, the HIF-system is also crucially involved in the pathogenesis of the renal cell carcinoma associated with the deficiency of the von Hippel-Lindau protein. However, it is not known which specific genes and pathways are involved in organ protection or cell dedifferentiation and whether the effects observed in animal models are relevant for humans. Therefore, this project aims to modulate the HIF-system in primary human tubular cells and in the kidney and to thoroughly analyze the genome-wide transcriptional HIF-response. Using modern high-throughput sequencing technologies, HIF DNA-binding sites, prominent regulatory DNA-elements and changes in transcriptional regulation will be analyzed in humans and related to conserved genetic elements in other species. Because the HIF system can in principle be induced by blocking HIF prolyl hydroxylases pharmacologically, these investigations bear important implications for the treatment of acute or chronic renal failure.