Yang Ying, Zhang Dong-Mei, Liu Jia-Hui, Hu Lin-Shui, Xue Qiao-Chu, Ding Xiao-Qin, Kong Ling-Dong
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210023, People׳s Republic of China.
Zhejiang Key Laboratory of Traditional Chinese Medicine Pharmaceutical Technology, Zhejiang CONBA Pharmaceutical Co., LTD, Lanxi 321109, People׳s Republic of China.
J Ethnopharmacol. 2015 Jul 1;169:49-59. doi: 10.1016/j.jep.2015.04.011. Epub 2015 Apr 23.
Wuling San, a famous prescription in Chinese medicine, is composed of Polyporus, Poria, Alismatis rhizoma, Cinnamomi cortex and Atractylodis macrocephalae rhizoma, and promotes kidney function and diuresis. The main purpose of this study was to investigate its renal protective effect in high fructose-induced hyperuricemic mice.
ICR mice were fed with 30% fructose in drinking water for 6 weeks to induce hyperuricemia and renal dysfunction. Then mice were orally administrated for other 6 weeks with Wuling San (987, 1316, 1755 and 2340mg/kg), allopurinol (5mg/kg) and water daily, respectively. Serum and urine levels of uric acid, creatinine and blood urea nitrogen (BUN) were measured. Hematoxylin and eosin staining was used to assess renal histological changes. Renal interleukin (IL)-1β concentrations were measured using ELISA kit. Renal protein levels of organic ion transporters, as well as toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling and pyrin domain containing 3 (NLRP3) inflammasome were determined by Western blot assay.
Wuling San significantly decreased serum uric acid, creatinine and BUN levels, increased fractional excretion of uric acid (FEUA) in fructose-fed mice. It restored fructose-induced dysregulation of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), ATP-binding cassette subfamily G member 2 (ABCG2) and organic anion transporter 1 (OAT1), as well as organic cation transporter 1 (OCT1) and OCT2 in mice. Wuling San obviously alleviated infiltration of inflammation cells in kidney glomerulus of fructose-fed mice. Moreover, Wuling San suppressed the activation of TLR4/ MyD88 signaling to inhibit nuclear factor κB (NF-κB) signaling and mitogen-activated protein kinases (MAPKs) activation in fructose-fed mice. Additionally, Wuling San decreased NLRP3 inflammasome activation and IL-1β secretion in the kidney of fructose-fed mice.
Wuling San exerts renal protective effect by modulating renal organic ion transporters in fructose-induced hyperuricemic mice. The molecular mechanism of its action may be associated with the suppression of TLR4/MyD88 signaling and NLRP3 inflammasome activation to reduce IL-1β production in high fructose-induced hyperuricemic mice.
五苓散是中医名方，由茯苓、猪苓、泽泻、肉桂和白术组成，具有促进肾功能和利尿作用。本研究的主要目的是探讨其对高果糖诱导的高尿酸血症小鼠的肾脏保护作用。
给ICR小鼠饮用含30%果糖的水6周以诱导高尿酸血症和肾功能障碍。然后，小鼠分别每日口服五苓散（987、1316、1755和2340mg/kg）、别嘌醇（5mg/kg）和水，持续6周。检测血清和尿液中的尿酸、肌酐和血尿素氮（BUN）水平。采用苏木精-伊红染色评估肾脏组织学变化。使用ELISA试剂盒检测肾脏白细胞介素（IL）-1β浓度。通过蛋白质免疫印迹法测定肾脏中有机离子转运蛋白的水平，以及Toll样受体4（TLR4）/髓样分化因子88（MyD88）信号通路和含pyrin结构域的蛋白3（NLRP3）炎性小体。
五苓散显著降低了果糖喂养小鼠的血清尿酸、肌酐和BUN水平，增加了尿酸排泄分数（FEUA）。它恢复了果糖诱导的肾脏尿酸转运蛋白1（URAT1）、葡萄糖转运蛋白9（GLUT9）、ATP结合盒转运体G2（ABCG2）和有机阴离子转运蛋白1（OAT1）以及小鼠体内有机阳离子转运蛋白1（OCT1）和OCT2的失调。五苓散明显减轻了果糖喂养小鼠肾小球中的炎症细胞浸润。此外，五苓散抑制了果糖喂养小鼠中TLR4/MyD88信号通路的激活，从而抑制核因子κB（NF-κB）信号通路和丝裂原活化蛋白激酶（MAPKs）的激活。此外，五苓散降低了果糖喂养小鼠肾脏中NLRP3炎性小体的激活和IL-1β的分泌。
五苓散通过调节果糖诱导的高尿酸血症小鼠的肾脏有机离子转运蛋白发挥肾脏保护作用。其作用的分子机制可能与抑制TLR4/MyD88信号通路和NLRP3炎性小体的激活，从而减少高果糖诱导的高尿酸血症小鼠中IL-1β的产生有关。
