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A Murine Model of Irreversible and Reversible Unilateral Ureteric Obstruction
Published on: December 20, 2014
Axl-inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model
August Hoel1, Tarig Osman1, Fredrik Hoel2
1Department of Clinical Medicine, University of Bergen, Bergen, Norway.
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.
Insights
Bemcentinib, an Axl inhibitor, partially reverses mitochondrial dysfunction and gene expression changes caused by kidney obstruction in a mouse model of renal fibrosis.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Renal fibrosis, a hallmark of chronic kidney disease (CKD), is linked to mitochondrial dysfunction.
- Previous studies demonstrated that Bemcentinib, an Axl receptor tyrosine kinase inhibitor, mitigates fibrosis development.
- This study investigates Bemcentinib's impact on mitochondrial dysfunction in the context of renal fibrosis.
Purpose of the Study:
- To analyze the effects of Bemcentinib on mitochondrial dysfunction in a unilateral ureter obstruction (UUO) mouse model.
- To investigate the molecular mechanisms underlying Bemcentinib's therapeutic potential in renal fibrosis.
- To assess the impact of Bemcentinib on gene expression and metabolic pathways related to mitochondrial function.
Main Methods:
- Genome-wide transcriptomics analysis of kidney tissue from UUO and SHAM-operated mice treated with or without Bemcentinib.
- Analysis of key mitochondrial pathways including oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and the citric acid cycle (TCA).
- Serum metabolomics to evaluate amino acid profiles and functional assessment of mitochondrial biomass.
Main Results:
- Unilateral ureter obstruction (UUO) significantly dysregulated mitochondria-related pathways, reducing expression of OXPHOS, FAO, TCA, reactive oxygen species response, and amino acid metabolism genes.
- Bemcentinib treatment partially reversed these gene expression changes, increasing the expression of downregulated pathways.
- UUO increased AKT/PI3K signaling, which was inhibited by Bemcentinib. Mitochondrial biomass was reduced by UUO but restored by Bemcentinib.
- Serum metabolomics revealed a normalizing amino acid profile in UUO mice treated with Bemcentinib.
Conclusions:
- Unilateral ureter obstruction (UUO) surgery profoundly impacts mitochondrial function and related gene expression in the kidney.
- Bemcentinib, an Axl inhibitor, demonstrates a partial reversal of UUO-induced mitochondrial dysfunction and metabolic alterations.
- These findings highlight the role of Axl signaling in renal fibrosis and suggest Bemcentinib as a potential therapeutic agent for CKD.
