Wuling San protects kidney dysfunction by inhibiting renal TLR4/MyD88 signaling and NLRP3 inflammasome activation in high fructose-induced hyperuricemic mice
Wuling San protects kidney dysfunction by inhibiting renal TLR4/MyD88 signaling and NLRP3 inflammasome activation in high fructose-induced hyperuricemic mice
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DOI：
10.1016/j.jep.2015.04.011
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发表时间：
2015-07-01
影响因子：
5.4
通讯作者：
Kong, Ling-Dong
中科院分区：
文献类型：
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作者：
Yang, Ying;Zhang, Dong-Mei;Kong, Ling-Dong
民族药理学相关性：五苓散是由猪苓、茯苓、泽泻、黄柏、白术组成的名方，具有补肾利水的功效。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。材料与方法：ICR小鼠用30%果糖饮水喂养6周，诱导高尿酸血症和肾功能不全。分别灌胃给予五苓散（987、1316、1755、2340 mg/kg）、别嘌呤醇（5 mg/kg）和水，连续6周。测定血清和尿液中尿酸、肌酐和血尿素氮（BUN）水平。苏木精-伊红染色用于评估肾组织学变化。使用ELISA试剂盒测量肾白细胞介素（IL）-1 β浓度。结果：五灵散能显著降低果糖喂养小鼠的血尿酸、肌酐和尿素氮水平，增加尿酸排泄分数（FEuA），并能显著降低小鼠肾组织中有机离子转运蛋白、Toll样受体4（TLR 4）/髓样分化因子88（MyD 88）信号通路和Pyrin domain containing 3（NLRP 3）炎性小体的表达。在小鼠中，它恢复了果糖诱导的肾尿酸盐转运蛋白1（URAT 1）、葡萄糖转运蛋白9（GLUT 9）、ATP结合盒亚家族G成员2（ABCG 2）和有机阴离子转运蛋白1（OAT 1）以及有机阳离子转运蛋白1（OCT 1）和OCT 2的失调。五灵散能明显减轻果糖喂养小鼠肾小球内炎症细胞浸润。五灵散还能抑制TLR 4/MyD 88信号通路的激活，从而抑制果糖喂养小鼠的核因子-κ B（NF-κ B）信号通路和丝裂原活化蛋白激酶（MAPK）的激活。结论：五灵散通过调节果糖诱导的高尿酸血症小鼠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TLR 4/MyD 88信号传导和NLRP 3炎性体激活以减少高果糖诱导的高尿酸血症小鼠中IL-1 β的产生有关。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Ethnopharmacological relevance: 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.Materials and methods: 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 2340 mg/kg), allopurinol (5 mg/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)-1 beta 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.Results: 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 kappa B (NF-kappa B) signaling and mitogen-activated protein kinases (MAPKs) activation in fructose-fed mice. Additionally, Wuling San decreased NLRP3 inflammasome activation and IL-1 beta secretion in the kidney of fructose-fed mice.Conclusion: 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-1 beta production in high fructose-induced hyperuricemic mice. (C) 2015 Elsevier Ireland Ltd. All rights reserved.