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

作者：Anna Faivre, Romain Dissard, Willy Kuo, Thomas Verissimo, David Legouis, Grégoire Arnoux, Carolyn Heckenmeyer, Marylise Fernandez, Matthieu Tihy, Renuga Devi Rajaram, Vasiliki Delitsikou, Ngoc An Le, Bernhard Spingler, Bert Müller, Georg Shulz, Maja T. Lindenmeyer, Clemens D. Cohen, Joseph M. Rutkowski, Solange Moll, Carsten C. Scholz, Vartan Kurtcuoglu, Sophie de Seigneux · 发表于：Nephrology Dialysis Transplantation · 年份：2023 · DOI：10.1093/ndt/gfad075 · 被引用次数：5 · 研究领域：Cancer, Hypoxia, and Metabolism、Autophagy in Disease and Therapy、Advanced Glycation End Products research

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 have 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 (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-computed tomography imaging. We analysed a database of 217 CKD biopsies from stage 1 to 5 and we randomly collected 15 CKD biopsies of 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 filtrat...