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Evolution of hypoxia and hypoxia-inducible factor asparaginyl hydroxylase (FIH) regulation in chronic kidney disease

Publication date2023-04-24
First online date2023-04-24
Abstract

Background: The roles of hypoxia and hypoxia inducible factor (HIF) during chronic kidney disease (CKD) are much debated. Interventional studies with HIF-α activation in rodents yielded contradictory results. The HIF pathway is regulated by prolyl and asparaginyl hydroxylases; while prolyl hydroxylase inhibition is a well-known method to stabilize HIF-α, little is known about the effect asparaginyl hydroxylase Factor Inhibiting HIF inhibiting (FIH).

Methods: We used a model of progressive proteinuric CKD and a model of obstructive nephropathy with unilateral fibrosis. In these models, we assessed hypoxia with pimonidazole and vascularization with three-dimensional micro-CT imaging. We analyzed a database of 217 CKD biopsies from stage 1 to 5 and we randomly collected 15 CKD biopsies from various severity degrees to assess FIH expression. Finally, we modulated FIH activity in vitro and in vivo using a pharmacologic approach, to assess its relevance in CKD.

Results: In our model of proteinuric CKD, we show that early CKD stages are not characterized by hypoxia or HIF activation. At late CKD stages, some areas of hypoxia are observed, but these are not colocalizing with fibrosis. In mice and in humans, we observed a downregulation of the HIF pathway, together with an increased FIH expression in CKD, according to its severity. Modulating FIH in vitro affects cellular metabolism, as described previously. In vivo, pharmacologic FIH inhibition increases the glomerular filtration rate of control and CKD animals and is associated with a reduced development of fibrosis.

Conclusions: The causative role of hypoxia and HIF activation in CKD progression is questioned. A pharmacological approach of FIH downregulation seem promising in proteinuric kidney disease.

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Keywords
  • CKD
  • FIH
  • HIF
  • HIF1AN
  • Asparaginyl hydroxylase
  • Hypoxia
Citation (ISO format)
FAIVRE, Anna et al. Evolution of hypoxia and hypoxia-inducible factor asparaginyl hydroxylase (FIH) regulation in chronic kidney disease. In: Nephrology dialysis transplantation, 2023, p. gfad075. doi: 10.1093/ndt/gfad075
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ISSN of the journal0931-0509
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