桂枝汤对高尿酸血症小鼠肾保护作用的研究

Study on Renal Protection of Gui-Zhi Decoction in Hyperuricemic Mice

目的:研究桂枝汤对高尿酸血症小鼠肾保护作用及其机制。方法:用氧嗪酸钾诱导小鼠产生高尿酸血症模型,并随机分为6组:空白对照组、模型对照组、别嘌呤醇组(5 mg·kg^(-1))、桂枝汤组(900、1 799和3 598 mg·kg^(-1))。苏木精-伊红染色观察小鼠肾脏组织病理学变化;商品化试剂盒测定小鼠血清和尿液中尿酸、肌酐和尿素氮水平以及肝脏黄嘌呤氧化酶(XOD)活性。采用Western blot方法检测动物肾脏尿酸盐转运子(URAT1)、葡萄糖转运子9(GLUT9)、三磷酸腺苷结合转运蛋白G超家族成员2(ABCG2)、有机阳离子转运子1(OCT1)、OCT2、有机阳离子/肉毒碱转运子1(OCTN1)和OCTN2。结果:与模型对照组比较,桂枝汤可明显降低高尿酸血症小鼠血清尿酸、肌酐和尿素氮水平,增加尿液尿酸和肌酐浓度,提高尿酸排泄分数。另外,桂枝汤可有效抑制高尿酸血症小鼠肝脏XOD活性,下调模型动物肾脏URAT1和GLUT9蛋白水平,上调肾脏ABCG2、OCT1、OCT2、OCTN1和OCTN2蛋白水平。结论:桂枝汤可能通过抑制高尿酸血症小鼠肝脏XOD活性以减少尿酸生成、调节肾脏有机离子转运子蛋白水平以促进尿酸及其他有机离子排泄,从而发挥其降尿酸和肾保护作用。

This study was aimed to investigate renal protective effects and mechanism of Gui-Zhi（GZ） decoction in hyperuricemic mice. Potassium oxonate was used to induce hyperuricemia mouse model. Mice were randomly divided into 6 groups, which were the blank control group, model group, allopurinol group（5 mg·kg-1） and GZ decoction group（900, 1 799 and 3 598 mg·kg-1）. Hematoxylin eosin staining was used to observe the histopathological changes of renal tissues in mice. Commercial assay kits were used to measure levels of uric acid（UA）, creatinine（Cr） and blood urea nitrogen（BUN） in serum and urine, as well as the xanthine oxidase（XOD） activity in liver. Renal protein levels of urate transporter 1（URAT1）, glucose transporter 9（GLUT9）, ATP-binding cassette G member 2（ABCG2）, organic cation transporter 1（OCT1）, OCT2, organic cation/carnitine transporter 1（OCTN1） and OCTN2 were detected by western blot. The results showed that compared with the model group, GZ decoction can obviously decrease serum levels of UA, Cr and BUN, increase urine levels of UA and Cr, resulting in the elevation of fractional excretion of UA in hyperuricemic mice. Additionally, GZ decoction obviously inhibited hepatic XOD activity in hyperuricemic mice. Furthermore, GZ decoction downregulated renal URAT1 and GLUT9 protein levels, upregulated renal ABCG2, as well as OCT1, OCT2, OCTN1 and OCTN2 protein levels in hyperuricemic mice. It was concluded that GZ decoction had hypouricemic and renal protective effects in hyperuricemic mice, which might be associated with the reduction of UA production via inhibiting hepatic XOD activity, promoting UA and other organic ion excretion via regulating renal organic ion transporter protein levels.