Deputy manager Shanghai Model Organisms Center Shanghai, China (People's Republic)
Disclosure(s):
Leon Xu: No relevant disclosure to display
Introduction/Rationale: Hyperuricemia (HUA), characterized by elevated serum uric acid (UA) levels, is a metabolic disorder arising from abnormalities in purine metabolism. It is closely associated with gout and renal disease including inflammation. Most mammals, including mice, maintain low serum urate concentrations because the functional hepatic urate oxidase (uricase, UOX) degrades UA into allantoin. In contrast, humans and apes lost uricase during hominoid evolution, rendering them susceptible to HUA. Therefore, inactivation of the Uox gene in mice provides an ideal “human-like” model for HUA.
Methods: We generated two uricase-deficient mouse models: a global Uox knockout (Uox-KO) and a liver-specific Uoxflox/flox; Alb-Cre (Uox-cKO) line, using the CRISPR/Cas9 system. Genotyping and immunoblot analyses were performed to determine the success of gene targeting and the absence of UOX protein expression. Subsequently, we assessed whether the UOX-KO and Uox-cKO mice exhibited spontaneous hyperuricemia phenotypes using ELISA, biochemical assays and pathological examination. Finally, we investigated the efficacy of allopurinol—a xanthine oxidase inhibitor commonly used in clinical practice in these UOX deficient mice.
Results: The deletion of Uox were confirmed in our UOX-KO and Uox-cKO mice. Both models exhibited spontaneously elevated circulating UA levels and developed severe nephropathy, characterized by increased blood urea nitrogen (BUN) and creatinine levels, renal swelling, fibrosis and inflammatory cell infiltration, recapitulating the key features of human HUA-associated nephropathy. Moreover, allopurinol treatment significantly reduced serum UA level and improved renal injury in the Uox knockout mice, validating their pharmacological responsiveness.
Conclusion: Together, these Uox-KO and Uox-cKO mice provide reliable models for investigating the mechanisms underlying hyperuricemia and evaluating potential therapies.
