Xor Risk Variants Predispose Mice to Fructose-Mediated Metabolic Dysfunction-Induced Kidney Injury

Background: Dietary patterns and genetics have fueled the metabolic syndrome health crisis, which has increased type 2 diabetes, a major cause of chronic kidney disease (CKD). Compelling evidence shows that overconsumption of fructose drives metabolic syndrome via insulin resistance, impaired lipid metabolism, and increased xanthine oxidase activity, which are deleterious to kidneys. Additionally, recent seminal studies from our lab reported that Xor risk variants are associated with metabolic and kidney diseases in humans. Importantly, these identified Xor risk variants are a binding site C/EBPβ, which mediates increased Xor activity and expression and CKD in susceptible diabetic DBA/2J and B6Xorem1 compared to resistant C57BL/6J (B6) mice. However, the role of Xor risk variants in driving kidney injury due to fructose-induced metabolic syndrome has not been investigated. Therefore, we hypothesized that high-risk Xor variants can potentiate the effects of fructose on Xor activity and drive renal injury. Methods: We grouped B6 and B6Xorem1 mice as normal water controls or to receive 30% fructose water, with/without the XOR inhibitor, febuxostat, for 6 months. At the end of the study, insulin resistance and protein excretion were measured. We collected blood and kidneys to measure C/EBPβ expression, Xor activity and expression, glomerular and tubular injury, and ectopic renal lipid accumulation. Metabolomics and RT-PCR were done on mouse kidneys to investigate kidney metabolic pathways involved in response to fructose. Results: Chronic fructose overconsumption significantly increased C/EBPβ and Xor expression in fructose-fed B6Xorem1 compared to fructose-fed B6 mice. Importantly, fructose-fed B6Xorem1 mice displayed oxidative stress, insulin resistance, renal lipid accumulation, and tubular injury characterized by tubular vacuolization and dilation and loss of brush borders compared to fructose-fed B6 mice, and these pathological changes were associated with upregulated de novo lipogenesis pathways. Xor blockade improved this phenotype, supporting the role of Xor activity in predisposition to kidney injury by fructose. Conclusion: Xor risk variants predispose to severe tubular injury induced by fructose-mediated -metabolic dysfunction by influencing pathways involved in de novo lipogenesis which can lead to lipid accumulation and oxidative stress. Funding: NIDDK Support