1383-P: Lipotoxic Kidney Injury by Fructose Is Mediated through High Risk XOR Variants

by sugaradmin



Introduction and Objective: The overconsumption of fructose-rich western diets can cause metabolic dysfunction-associated kidney disease (MDAKD). We recently reported that high-risk Xor variants increase Xor and predispose to kidney disease in susceptible DBA/2J and B6Xorem1 vs. resistant C57BL/6J (B6) mice, with diabetes. However, the role of Xor risk variants in fructose-induced MDAKD has not been investigated. Therefore, the objective of this study was to determine whether high-risk Xor variants confer susceptibility to fructose-induced MDAKD.Methods: We randomly grouped B6 and B6Xorem1 mice either as controls (normal water) or to receive 30% fructose ± the Xor inhibitor, febuxostat/day for 6 mo. At the end of the study, insulin resistance and albuminuria were measured, after which mice were euthanized and blood and kidneys collected to measure the expression of Xor, as well as lipogenic transcription factors and enzymes, glomerular and tubular injury and ectopic lipid accumulation. Metabolomics was performed on mouse kidneys to measure small metabolites and lipid species, while electron paramagnetic resonance spectroscopy was used to measure lipid-derived free radicals in response to chronic fructose overconsumption. Data analysis was done with one-way ANOVA, and P < 0.05 was considered significant.Results: Chronic fructose intake increased Xor, ChREBPβ, and lipogenic enzymes in fructose-fed B6Xorem1 vs. B6 mice, and this was associated with increased activation of purine metabolism and triglyceride biosynthesis pathways. Importantly, fructose-fed B6Xorem1 displayed insulin resistance, microalbuminuria, kidney lipotoxicity, increased lipid radicals and severe tubular injury vs. fructose-fed B6 mice, and these pathophysiologic changes were ameliorated by Xor inhibition in fructose-fed B6Xorem1 mice.Conclusion: We show for the first time that susceptibility to fructose-induced MDAKD with a severe fatty kidney phenotype is mediated by Xor in mice with high-risk Xor variants.

Disclosure

U.S. Ekperikpe: None. S. Zhao: None. L. Yu: None. K. Stadler: None. I.S. Daehn: None.

Funding

NIH: R01DK097253NIH: R01DK139395NIH: TL1DK136048



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