Diabetes Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China.
J Ethnopharmacol. 2023 Aug 10;312:116530. doi: 10.1016/j.jep.2023.116530. Epub 2023 Apr 23.
Simiao San (SmS), a famous traditional Chinese formula, is clinically used to treat patients with hyperuricemia (HUA). However, its mechanism of action on lowering uric acid (UA) and inhibiting inflammation still deserves further investigation.
To examine the effect and its possible underlying mechanism of SmS on UA metabolism and kidney injury in HUA mouse.
The HUA mouse model was constructed with the combined administration of both potassium oxalate and hypoxanthine. The effects of SmS on UA, xanthine oxidase (XOD), creatinine (CRE), blood urea nitrogen (BUN), interleukin-10 (IL-10), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined by ELISA or biochemical assays. Hematoxylin and eosin (H&E) was used to observe pathological alterations in the kidneys of HUA mice. The expression levels of organic anion transporter 1 (OAT1), recombinant urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), nucleotide binding domain and leucine rich repeat pyrin domain containing 3 (NLRP3), Cleaved-Caspase 1, apoptosis-associated speck like protein (ASC), nuclear factor kappa-B (NF-κB), IL-6, janus kinase 2 (JAK2), phosphor (P)-JAK2, signal transducers and activators of transcription 3 (STAT3), P-STAT3, suppressor of cytokine signaling 3 (SOCS3) were examined by Western blot and/or immunohistochemical (IHC) staining. The major ingredients in SmS were identified by a HPLC-MS assay.
HUA mouse exhibited an elevation in serum levels of UA, BUN, CRE, XOD, and the ratio of urinary albumin to creatinine (UACR), and a decline in urine levels of UA and CRE. In addition, HUA induces pro-inflammatory microenvironment in mouse, including an increase in serum levels of IL-1β, IL-6, and TNF-α, and renal expressions of URAT1, GULT9, NLRP3, ASC, Cleaved-Caspase1, P-JAK2/JAK2, P-STAT3/STAT3, and SOCS3, and a decrease in serum IL-10 level and renal OAT1 expression as well as a disorganization of kidney pathological microstructure. In contrast, SmS intervention reversed these alterations in HUA mouse.
SmS could alleviate hyperuricemia and renal inflammation in HUA mouse. The action mechanisms behind these alterations may be associated with a limitation of the NLRP3 inflammasome and JAK2/STAT3 signaling pathways.
四妙散（SmS）是一种著名的中药方剂，临床上用于治疗高尿酸血症（HUA）患者。然而，其降低尿酸（UA）和抑制炎症的作用机制仍有待进一步研究。
研究 SmS 对 HUA 小鼠尿酸代谢和肾脏损伤的作用及其可能的机制。
采用联合给予草酸盐和次黄嘌呤的方法构建 HUA 小鼠模型。通过 ELISA 或生化测定法测定 SmS 对 UA、黄嘌呤氧化酶（XOD）、肌酐（CRE）、血尿素氮（BUN）、白细胞介素-10（IL-10）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的影响。用苏木精和伊红（H&E）观察 HUA 小鼠肾脏的病理改变。用 Western blot 和/或免疫组化（IHC）染色法检测有机阴离子转运蛋白 1（OAT1）、重组尿酸转运蛋白 1（URAT1）、葡萄糖转运蛋白 9（GLUT9）、核苷酸结合域和富含亮氨酸重复的吡咯烷域包含 3（NLRP3）、Cleaved-Caspase 1、凋亡相关斑点样蛋白（ASC）、核因子 kappa-B（NF-κB）、IL-6、Janus 激酶 2（JAK2）、磷酸化（P）-JAK2、信号转导和转录激活因子 3（STAT3）、P-STAT3、细胞因子信号转导抑制因子 3（SOCS3）的表达水平。用 HPLC-MS 法鉴定 SmS 中的主要成分。
HUA 小鼠血清 UA、BUN、CRE、XOD 水平升高，尿 UA 和 CRE 水平降低，尿白蛋白与肌酐比值（UACR）升高。此外，HUA 诱导了小鼠的促炎微环境，包括血清中 IL-1β、IL-6 和 TNF-α水平升高，肾脏中 URAT1、GULT9、NLRP3、ASC、Cleaved-Caspase1、P-JAK2/JAK2、P-STAT3/STAT3 和 SOCS3 表达升高，血清中 IL-10 水平和肾脏 OAT1 表达降低，肾脏病理结构紊乱。相反，SmS 干预逆转了 HUA 小鼠的这些改变。
SmS 可减轻 HUA 小鼠的高尿酸血症和肾脏炎症。这些变化的作用机制可能与 NLRP3 炎症小体和 JAK2/STAT3 信号通路的限制有关。
