학술논문
Axl-inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model.
Document Type
Academic Journal
Author
Hoel A; Department of Clinical Medicine, University of Bergen, Bergen, Norway.; Osman T; Department of Clinical Medicine, University of Bergen, Bergen, Norway.; Hoel F; Department of Biomedicine, University of Bergen, Bergen, Norway.; Elsaid H; Department of Clinical Medicine, University of Bergen, Bergen, Norway.; Chen T; Department of Clinical Medicine, University of Bergen, Bergen, Norway.; Landolt L; Department of Clinical Medicine, University of Bergen, Bergen, Norway.; Babickova J; Department of Clinical Medicine, University of Bergen, Bergen, Norway.; Faculty of Medicine, Institute of Molecular Biomedicine, Comenius University in Bratislava, Bratislava, Slovakia.; Tronstad KJ; Department of Biomedicine, University of Bergen, Bergen, Norway.; Lorens JB; BerGenBio ASA, Bergen, Norway.; Department of Biomedicine, Center for Cancer Biomarkers, University of Bergen, Bergen, Norway.; Gausdal G; BerGenBio ASA, Bergen, Norway.; Marti HP; Department of Clinical Medicine, University of Bergen, Bergen, Norway.; Department of Medicine, Haukeland University Hospital, Bergen, Norway.; Furriol J; Department of Clinical Medicine, University of Bergen, Bergen, Norway.; Department of Medicine, Haukeland University Hospital, Bergen, Norway.
Source
Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101083777 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1582-4934 (Electronic) Linking ISSN: 15821838 NLM ISO Abbreviation: J Cell Mol Med Subsets: MEDLINE
Subject
Language
English
Abstract
Renal fibrosis is a progressive histological manifestation leading to chronic kidney disease (CKD) and associated with mitochondrial dysfunction. In previous work, we showed that Bemcentinib, an Axl receptor tyrosine kinase inhibitor, reduced fibrosis development. In this study, to investigate its effects on mitochondrial dysfunction in renal fibrosis, we analysed genome-wide transcriptomics data from a unilateral ureter obstruction (UUO) murine model in the presence or absence of bemcentinib (n = 6 per group) and SHAM-operated (n = 4) mice. Kidney ligation resulted in dysregulation of mitochondria-related pathways, with a significant reduction in the expression of oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), citric acid cycle (TCA), response to reactive oxygen species and amino acid metabolism-related genes. Bemcentinib treatment increased the expression of these genes. In contrast, AKT/PI3K signalling pathway genes were up-regulated upon UUO, but bemcentinib largely inhibited their expression. At the functional level, ligation reduced mitochondrial biomass, which was increased upon bemcentinib treatment. Serum metabolomics analysis also showed a normalizing amino acid profile in UUO, compared with SHAM-operated mice following bemcentinib treatment. Our data suggest that mitochondria and mitochondria-related pathways are dramatically affected by UUO surgery and treatment with Axl-inhibitor bemcentinib partially reverses these effects.
(© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
(© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)