Xue Lina, Tao Qianru, Chang Haining, Yan Shu, Wang Lei, Zhao Zefang, Tu Chao
Department of Internal Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People's Republic of China.
Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People's Republic of China.
J Inflamm Res. 2025 Jan 3;18:17-30. doi: 10.2147/JIR.S500101. eCollection 2025.
Serum uric acid (SUA) is primarily produced through the hydrolysis of purines in the liver, with its excretion largely handled by the kidneys. Urate transporter 1 (URAT1) inhibitors are known to enhance uric acid elimination via the kidneys, but they also increase the risk of kidney stone formation. Currently, xanthine oxidase (XO) inhibitors are the predominant uric-lowering medications on the market.
In this study, we utilized single-cell RNA sequencing, spatial metabolomics, plasma metabolomics, flow cytometry to explore the effects of Tigulixostat on uric acid level and hyperuricemic nephropathy (HN) in Uox-KO mouse model.
In this study, we discovered that Tigulixostat (LC350189) more effectively reduced SUA levels and resulted in better renal outcomes compared to allopurinol, without inducing liver injury in urate oxidase knockout (Uox-KO) mice. Mechanistically, we found that Tigulixostat improved HN by promoting M2 macrophage polarization.
These findings suggest Tigulixostat as a promising therapeutic option for managing hyperuricemia and related kidney conditions.
血清尿酸（SUA）主要通过肝脏中嘌呤的水解产生，其排泄主要由肾脏负责。已知尿酸转运蛋白1（URAT1）抑制剂可通过肾脏增强尿酸清除，但它们也会增加肾结石形成的风险。目前，黄嘌呤氧化酶（XO）抑制剂是市场上主要的降尿酸药物。
在本研究中，我们利用单细胞RNA测序、空间代谢组学、血浆代谢组学、流式细胞术来探究替古利司他对尿酸氧化酶基因敲除（Uox-KO）小鼠模型中尿酸水平和高尿酸血症肾病（HN）的影响。
在本研究中，我们发现与别嘌醇相比，替古利司他（LC350189）能更有效地降低SUA水平，并带来更好的肾脏结局，且在尿酸氧化酶基因敲除（Uox-KO）小鼠中不会引起肝损伤。从机制上来说，我们发现替古利司他通过促进M2巨噬细胞极化改善高尿酸血症肾病。
这些发现表明替古利司他是治疗高尿酸血症及相关肾脏疾病的一个有前景的治疗选择。
