Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, Qingdao, China; Institute of Metabolic Diseases, Qingdao University, Qingdao, China.
Institute of Metabolic Diseases, Qingdao University, Qingdao, China; Department of Endocrinology and Metabolic Diseases, the Affiliated Hospital of Qingdao University, Qingdao, China.
Kidney Int. 2018 Jan;93(1):69-80. doi: 10.1016/j.kint.2017.04.031. Epub 2017 Jul 18.
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.
尿酸氧化酶（Uox）基因编码尿酸酶，在啮齿动物肝脏中将尿酸降解为尿囊素，这成为建立稳定高尿酸血症小鼠模型的障碍。灵长类动物进化过程中人类尿酸酶的缺失导致其易患高尿酸血症。因此，我们使用转录激活样效应物核酸酶（TALEN）技术在纯 C57BL/6J 背景下生成了 Uox 基因敲除小鼠模型。这些 Uox 基因敲除小鼠自发出现高尿酸血症（超过 420 μmol/l），在 62 周时约有 40%的存活率。在这些 Uox 基因敲除小鼠中观察到肾功能障碍（血清肌酐和血尿素氮升高）和肾小球/肾小管病变。雄性 Uox 基因敲除小鼠出现糖代谢紊乱，与胰岛素分泌受损和对链脲佐菌素诱导的糖尿病易感性增加有关，而雌性小鼠则出现高血压伴异常脂肪代谢。尿酸降低药物可降低血清尿酸水平并改善高尿酸血症引起的疾病。因此，尿酸酶敲除提供了一种合适的小鼠模型，可用于研究模拟人类状况的高尿酸血症及相关疾病，表明高尿酸血症在代谢紊乱和高血压的发展中起因果作用。
