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

Autor:	Faivre A; Department of Medicine and Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland.; Service of Nephrology, Department of Medicine, Geneva University Hospitals, Geneva, Switzerland., Dissard R; Department of Medicine and Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland., Kuo W; Institute of Physiology, University of Zurich, Zurich, Switzerland.; National Centre of Competence in Research, Kidney. CH, University of Zurich, Zurich, Switzerland., Verissimo T; Department of Medicine and Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland., Legouis D; Department of Medicine and Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland.; Division of Intensive Care, Department of Acute Medicine, Geneva University Hospitals, Geneva, Switzerland., Arnoux G; Department of Medicine and Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland.; Service of Clinical Pathology, Department of Pathology and Immunology, University Hospitals and University of Geneva, Geneva, Switzerland., Heckenmeyer C; Department of Medicine and Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland., Fernandez M; Department of Medicine and Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland., Tihy M; Service of Clinical Pathology, Department of Pathology and Immunology, University Hospitals and University of Geneva, Geneva, Switzerland., Rajaram RD; Department of Medicine and Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland., Delitsikou V; Department of Medicine and Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland., Le NA; Department of Chemistry, University of Zurich, Zurich, Switzerland., Spingler B; Department of Chemistry, University of Zurich, Zurich, Switzerland., Mueller B; Biomaterials Science Center, Department of Biomedical Engineering, University of Basel, Allschwil, Switzerland., Shulz G; Biomaterials Science Center, Department of Biomedical Engineering, University of Basel, Allschwil, Switzerland.; Micro- and Nanotomography Core Facility, Department of Biomedical Engineering, University of Basel, Allschwil, Switzerland., Lindenmeyer M; III Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Cohen C; Nephrological Center, Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany., Rutkowski JM; Department of Medical Physiology, Texas A&M University Health Science Center, Bryan, TX, USA., Moll S; Service of Clinical Pathology, Department of Pathology and Immunology, University Hospitals and University of Geneva, Geneva, Switzerland., Scholz CC; Institute of Physiology, University of Zurich, Zurich, Switzerland.; National Centre of Competence in Research, Kidney. CH, University of Zurich, Zurich, Switzerland.; Institute of Physiology, University Medicine Greifswald, Greifswald, Germany., Kurtcuoglu V; Institute of Physiology, University of Zurich, Zurich, Switzerland.; National Centre of Competence in Research, Kidney. CH, University of Zurich, Zurich, Switzerland., de Seigneux S; Department of Medicine and Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland.; Service of Nephrology, Department of Medicine, Geneva University Hospitals, Geneva, Switzerland.; National Centre of Competence in Research, Kidney. CH, University of Zurich, Zurich, Switzerland.
Jazyk:	angličtina
Zdroj:	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association [Nephrol Dial Transplant] 2023 Sep 29; Vol. 38 (10), pp. 2276-2288.
DOI:	10.1093/ndt/gfad075
Abstrakt:	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 filtration rate of control and CKD animals and is associated with decreased development of fibrosis. Conclusions: The causative role of hypoxia and HIF activation in CKD progression is questioned. A pharmacological approach of FIH downregulation seems promising in proteinuric kidney disease. (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)
Databáze:	MEDLINE
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