Identifying biochemical changes in the kidney using proton nuclear magnetic resonance in an adenine diet chronic kidney disease mouse model

• Published in: NMR in biomedicine 2024-12, Vol.37 (12), p.e5257-n/a
• Main Authors: Humphries, Tyrone L. R., Gobe, Glenda C., Urquhart, Aaron J., Ellis, Robert J., Galloway, Graham J., Vesey, David A., Francis, Ross S.
• Format: Article
• Language: English
• Subjects: 2D‐COSY; Adenine; Animal models; Animal tissues; Animals; Biomarkers; chronic kidney disease; Damage assessment; Diet; Disease Models, Animal; Enzymes; Fatty acids; Fibrosis; Genes; Glycolysis; Histopathology; Inflammation; Kidney - diagnostic imaging; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidneys; Lipid metabolism; Lipids; Magnetic resonance spectroscopy; Male; Metabolic pathways; Metabolism; Metabolites; Metabolome; metabonomics; Mice; Mice, Inbred C57BL; NMR; NMR spectroscopy; Nuclear magnetic resonance; Oxidation; Polymerase chain reaction; Proton Magnetic Resonance Spectroscopy; proximal tubular epithelial cells; Recovery; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; Triglycerides; Two dimensional analysis
• ISSN: 0952-3480; 1099-1492; 1099-1492
• DOI: 10.1002/nbm.5257

This study aimed to investigate the metabolic changes in the kidneys in a murine adenine–diet model of chronic kidney disease (CKD). Kidney fibrosis is the common pathological manifestation across CKD aetiologies. Sustained inflammation and fibrosis cause changes in preferred energy metabolic pathways in the cells of the kidney. Kidney cortical tissue from mice receiving a control or adenine‐supplemented diet for 8 weeks (late inflammation and fibrosis) and 12 weeks (8 weeks of treatment followed by 4 weeks recovery) were analysed by 2D‐correlated nuclear magnetic resonance spectroscopy and compared with histopathology and biomarkers of kidney damage. Tissue metabolite and lipid levels were assessed using the MestreNova software. Expression of genes related to inflammation, fibrosis, and metabolism were measured using quantitative polymerase chain reaction. Animals showed indicators of severely impaired kidney function at 8 and 12 weeks. Significantly increased fibrosis was present at 8 weeks but not in the recovery group suggesting some reversal of fibrosis and amelioration of inflammation. At 8 weeks, metabolites associated with glycolysis were increased, while lipid signatures were decreased. Genes involved in fatty acid oxidation were decreased at 8 weeks but not 12 weeks while genes associated with glycolysis were significantly increased at 8 weeks but not at 12 weeks. In this murine model of CKD, kidney fibrosis was associated with the accumulation of triglyceride and free lactate. There was an up‐regulation of glycolytic enzymes and down‐regulation of lipolytic enzymes. These metabolic changes reflect the energy demands associated with progressive kidney disease where there is a switch from fatty acid oxidation to that of glycolysis. A whole tissue metabonomic and gene expression analysis of diseased kidney tissue used an adenine diet‐induced chronic kidney disease mouse model. Evidence observed of decreased utilisation of fatty acid oxidation and increased reliance of glycolysis by the cell of the kidney under disease conditions.