Systematic metabolomic study on the plasma and urine of a mouse model of Alport syndrome.

Chronic kidney disease (CKD) progression involves metabolic alterations that remain poorly understood. We conducted a comprehensive metabolomic study by using an Alport syndrome (AS) mouse model, which is a hereditary form of CKD characterized by progressive nephropathy and hearing loss, to identify key metabolic disturbances associated with disease progression. Plasma and urine samples were collected from male Col4a3 knockout (AS) and wild-type mice at 4 and 7 weeks and analyzed using gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry. We identified 28 plasma and 42 urine metabolites that differed significantly (p < 0.05, VIP > 1.0 by PLS-DA) between AS and wild-type groups. At 4 weeks, the levels of metabolites involved in glycolysis/gluconeogenesis and the TCA cycle increased in the AS mice. By 7 weeks, the pathways related to amino acid metabolism (e.g., tryptophan metabolism and alanine, aspartate, and glutamate metabolism) and ketone body metabolism were significantly disrupted. Notably, palmitic acid and 5-methylcytidine emerged as potential biomarkers of disease progression. Our study provided novel insights into metabolic dysregulation and highlighted specific metabolites as potential biomarkers for early diagnosis and disease monitoring of CKD. These results might facilitate the development of targeted metabolic interventions for CKD.