4.7 Article

Kidney and plasma metabolomics provide insights into the molecular mechanisms of urate nephropathy in a mouse model of hyperuricemia

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ELSEVIER
DOI: 10.1016/j.bbadis.2022.166374

Keywords

Hyperuricemia; Uricase oxidase; Metabolomics; Urate nephropathy; Metabolite biomarkers

Funding

  1. National Natural Science Foundation of China [81770869, 81900636]

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Hyperuricemia (HUA) is closely linked to kidney damage and diseases, but the underlying mechanisms of HUA-induced kidney diseases are still unknown. In this study, a HUA mouse model was created by knocking out the urate oxidase (Uox) gene, and the kidney and plasma metabolic profiles were examined. The results revealed disturbances in purine metabolism, amino acid biosynthesis, tryptophan metabolism, and neuroactive ligand-receptor interaction in the Uox-Ko mice. Betaine and biotin were identified as potential plasma metabolic biomarkers for predicting urate nephropathy (UN).
Hyperuricemia (HUA) is closely associated with kidney damage and kidney diseases in humans; however, the underlying mechanisms of HUA-induced kidney diseases remain unknown. In the present study, we examined the kidney and plasma metabolic profiles in a HUA mouse model constructed by knocking out (Ko) the urate oxidase (Uox) gene. The Uox-Ko mice were characterized by an increase in uric acid, glycine, 3'-adenosine mono-phosphate, citrate, N-acetyl-L-glutamate, L-kynurenine, 5-hydroxyindoleacetate, xanthurenic acid, cortisol, and (-)-prostaglandin e2 together with a decrease of inosine in the kidneys. These altered metabolites confirmed disturbances of purine metabolism, amino acid biosynthesis, tryptophan metabolism, and neuroactive ligand-receptor interaction in Uox-Ko mice. Betaine and biotin were related to kidney function and identified as the potential plasma metabolic biomarker for predicting urate nephropathy (UN). Taken together, these results revealed the underlying pathogenic mechanisms of UN. Investigating these pathways might provide novel targets for the therapeutic intervention of UN and can potentially lead to new treatment strategies.

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