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

• Applicant: Dr. Johannes Schödel, Ph.D.
• Subject Area: Nephrology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 251104637

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.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Participating Person: Professor Dr. Peter J Ratcliffe