Tubuloprotection by Inhibition of the HIF-asparaginyl hydroxylase

• Applicant: Dr. Steffen Grampp
• Subject Area: Nephrology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457315198

The frequency of acute kidney injury (AKI) in hospitalized patients is increasing. In AKI, reduced bloodflow and insufficient oxygen supply leads to tissue hypoxia, which subsequently causes death of tubular epithelial cells. Currently there are no specific pharmacological treatment strategies for AKI. However, there is a great body of evidence from animal studies suggesting that preconditional stabilization of hypoxia inducible factors (HIF) in renal tubular epithelial cells, protects from tissue damage and preserves kidney function. Beside other signals, HIF targets important pathways such as glucose and lipid metabolism, angiogenisis and cell cycle. The introduction of HIF stabilizing compounds for therapy of the anemia in renal patients underscores the great potential of HIF-signaling for the treatment of kidney diseases. The new compounds are inhibitors of prolyl hydroxylases (PHDI), which regulate the stability of HIF. A second important regulatory mechanism, which decreases HIF activity by FIH mediated asparaginyl hydroxylation is unaffected by these compounds. Aim of my project is to explore the effect of a short-term use of PHD and FIH inhibitors in human renal tubular cells and experimental models of AKI. I hypothesize that maximizing HIF activity will optimize kidney protection. With use of modern sequencing methods, I will define kidney-specific HIF and FIH targets and identify potential candidate pathways mediating the nephroprotective effect of HIF in AKI.

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