Project 8: Mechanisms of up- and downstream of hypoxia-inducible factor in acute kidney injury
According to the unifying hypothesis of Research Unit 1368 local renal hypoxia is a hallmark in acute kidney injury (AKI). Remarkably, adaptation to hypoxia via hypoxia-inducible factor (HIF) remains incomplete. HIF transcription factors are master regulators of the cellular adaptation to hypoxia. HIF target genes are involved in a complex regulatory network governing metabolism, cell cycle, vascular tone, pH regulation, erythropoiesis, scavenging of free radicals, angiogenesis etc. The mechanisms behind insufficient HIF activation in AKI remain to be unravelled, and will be investigated in the proposed study. Glycerol injection into the hind limbs will be the principal AKI model, which is closely related to a major form of human AKI, rhabdomyolysis. HIF activation will be achieved by Pax8-rtTA based, tetracycline-inducible, and renal tubule-specific knockout of von Hippel-Lindau protein (VHL) in mice. We have demonstrated that this is a reliable tool for obtaining widespread and stable HIF activation in the entire nephron. Furthermore, we have shown that these transgenic mice are protected from rhabdomyolysis-induced AKI (Rh-AKI). Based on results of the first funding period we wish to test four major hypotheses regarding mechanisms up- and down-stream of HIF: 1) In AKI micro-RNAs (miRs) suppress HIF activation; 2) The benefit of HIF activation lies in its ability to enhance autophagy and 3) Glycolysis; and 4) AKI and HIF lead to epigenetic changes with implications on HIF target gene trans-activation.