Knockout of the urate oxidase gene provides a stable mouse model of hyperuricemia associated with metabolic disorders
Lu J, Hou X, Yuan X, Cui L, Liu Z, Li X, Ma L, Cheng X, Xin Y, Wang C, Zhang K, Wang X, Ren W, Sun R, Jia Z, Tian Z, Mi Q, Li C. Knockout of the urate oxidase gene provides a stable mouse model of hyperuricemia associated with metabolic disorders. Kidney international 2018; 93(1):69-80.
The urate oxidase (Uox) gene encodes uricase that in the rodent liver degrades uric acid into allantoin, forming an obstacle for establishing stable mouse models of hyperuricemia. The loss of uricase in humans during primate evolution causes their vulnerability to hyperuricemia. Thus, we generated a Uox-knockout mouse model on a pure C57BL/6J background using the transcription activator-like effector nuclease (TALEN) technique. These Uox-knockout mice spontaneously developed hyperuricemia (over 420 μmol/l) with about 40% survival up to 62 weeks. Renal dysfunction (elevated serum creatinine and blood urea nitrogen) and glomerular/tubular lesions were observed in these Uox-knockout mice. Male Uox-knockout mice developed glycol-metabolic disorders associated with compromised insulin secretion and elevated vulnerability to streptozotocin-induced diabetes, whereas female mice developed hypertension accompanied by aberrant lipo-metabolism. Urate-lowering drugs reduced serum uric acid and improved hyperuricemia-induced disorders. Thus, uricase knockout provides a suitable mouse model to investigate hyperuricemia and associated disorders mimicking the human condition, suggesting that hyperuricemia has a causal role in the development of metabolic disorders and hypertension.
Medical Subject Headings
Animals; Biomarkers; Blood Glucose; Blood Pressure; Blood Urea Nitrogen; Creatinine; Diabetes Mellitus, Experimental; Disease Models, Animal; Disease Progression; Dyslipidemias; Female; Genetic Predisposition to Disease; Gout Suppressants; Hypertension; Hyperuricemia; Insulin; Kidney; Lipids; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Time Factors; Urate Oxidase; Uric Acid