Institute of Metabolic Diseases, Qingdao University, Qingdao, China; Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, Qingdao, China.
CAS Key Laboratory of Nutrition, Metabolism, and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China, University of Chinese Academy of Sciences, Beijing, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Mar;1870(3):167009. doi: 10.1016/j.bbadis.2023.167009. Epub 2024 Jan 17.
Urate oxidase (Uox)-deficient mice could be an optimal animal model to study hyperuricemia and associated disorders. We develop a liver-specific conditional knockout Uox-deficient (Uox) mouse using the Cre/loxP gene targeting system. These Uox mice spontaneously developed hyperuricemia with accumulated serum urate metabolites. Blocking urate degradation, the Uox mice showed significant de novo purine biosynthesis (DNPB) in the liver along with amidophosphoribosyltransferase (Ppat). Pegloticase and allopurinol reversed the elevated serum urate (SU) levels in Uox mice and suppressed the Ppat up-regulation. Although urate nephropathy occurred in 30-week-old Uox mice, 90 % of Uox-deficient mice had a normal lifespan without pronounced urate transport abnormality. Thus, Uox mice are a stable model of human hyperuricemia. Activated DNPB in the Uox mice provides new insights into hyperuricemia, suggesting increased SU influences purine synthesis.
尿酸氧化酶（Uox）缺乏的小鼠可能是研究高尿酸血症和相关疾病的最佳动物模型。我们使用 Cre/loxP 基因靶向系统开发了一种肝脏特异性条件性敲除 Uox 缺陷（Uox）小鼠。这些 Uox 小鼠自发性地发展为高尿酸血症，伴有血清尿酸代谢物的积累。阻断尿酸降解后，Uox 小鼠肝脏中的从头嘌呤生物合成（DNPB）显著增加，同时伴有酰胺磷酸核糖基转移酶（Ppat）。佩格洛替卡酶和别嘌醇逆转了 Uox 小鼠中升高的血清尿酸（SU）水平，并抑制了 Ppat 的上调。尽管在 30 周龄的 Uox 小鼠中发生了尿酸肾病，但 90%的 Uox 缺陷小鼠具有正常的寿命，没有明显的尿酸转运异常。因此，Uox 小鼠是人类高尿酸血症的稳定模型。Uox 小鼠中激活的 DNPB 为高尿酸血症提供了新的见解，表明升高的 SU 影响嘌呤合成。
