Kidney Week

Abstract: TH-PO556

Detrimental Role of Hypoxia-Inducible Factor Asparaginyl Hydroxylase (FIH) in CKD

Session Information

• Pathology and Lab Medicine
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

• 1700 Pathology and Lab Medicine

Authors

• Faivre, Anna, Universite de Geneve Departement de physiologie cellulaire et metabolisme, Geneve, Genève, Switzerland

Anna Faivre,

• Dissard, Romain, Universite de Geneve Departement de physiologie cellulaire et metabolisme, Geneve, Genève, Switzerland

Romain Dissard,

• Kuo, Willy, Universitat Zurich Physiologisches Institut, Zurich, ZH, Switzerland

Willy Kuo,

• Verissimo, Thomas, Universite de Geneve Departement de physiologie cellulaire et metabolisme, Geneve, Genève, Switzerland

Thomas Verissimo,

• Legouis, David, Universite de Geneve Departement de physiologie cellulaire et metabolisme, Geneve, Genève, Switzerland

David Legouis,

• Arnoux, Gregoire, Universite de Geneve Departement de physiologie cellulaire et metabolisme, Geneve, Genève, Switzerland

Gregoire Arnoux,

• Lindenmeyer, Maja, Universitatsklinikum Hamburg-Eppendorf Zentrum fur Innere Medizin, Hamburg, Hamburg, Germany

Maja Lindenmeyer,

• Moll, Solange, Hopitaux Universitaires Geneve, Geneve, Genève, Switzerland

Solange Moll,

• Scholz, Carsten C., Universitat Zurich Physiologisches Institut, Zurich, ZH, Switzerland

Carsten C. Scholz,

• Kurtcuoglu, Vartan, Universitat Zurich Physiologisches Institut, Zurich, ZH, Switzerland

Vartan Kurtcuoglu,

• De Seigneux, Sophie M., Universite de Geneve Departement de physiologie cellulaire et metabolisme, Geneve, Genève, Switzerland

Sophie M. De Seigneux,

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 three prolyl and one asparaginyl hydroxylases; while prolyl hydroxylase inhibition is a well-known method to stabilize HIF-α, little is known about the effect of the inhibition of the asparaginyl hydroxylase Factor Inhibiting HIF (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 high-definition three-dimensional micro-CT imaging. We analyzed a database of 217 CKD biopsies from stage 1 to 5 for transcription 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 interestingly 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 vitroaffects 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.

Conclusion

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.