适宜中药筛选的高尿酸血症动物模型初探  

Adequate Animal Models of Hyperuricemia for Traditional Chinese Medicine Screening

作　　者：孟晶[1] 田婧卓 王连嵋[1] 赵雍[1] 李春英[1] 易艳[1] 张宇实[1] 韩佳寅[1] 潘辰[1] 刘素彦 鲜中 王敦方 秦莎莎 王芳 梁爱华[1] MENG Jing;TIAN Jing-zhuo;WANG Lian-mei;ZHAO Yong;LI Chun-ying;YI Yan;ZHANG Yu-shi;HAN Jia-yin;PAN Chen;LIU Su-yan;XIAN Zhong;WANG Dun-fang;QIN Sha-sha;WANG Fang;LIANG Ai-hua(Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China)

机构地区：[1]中国中医科学院中药研究所,北京100700

出　　处：《中国实验方剂学杂志》2021年第17期46-56,共11页Chinese Journal of Experimental Traditional Medical Formulae

基　　金：国家“重大新药创制”科技重大专项(2018ZX09101002-003);中国中医科学院课题(ZZ12-001,ZZ-13-035-10,GH201919);中药研究所自选课题(ZXKT19014,ZXKT20022)。

摘　　要：目的:将四种常用于中药筛选的高尿酸血症(HUA)动物模型进行比较研究,观察各模型特点,为筛选降尿酸中药及复方奠定模型基础。方法:54只雄性SD大鼠随机分为9组,分别为正常组、模型次黄嘌呤(HX)+氧嗪酸钾(OAPS)组、模型酵母膏(YE)+OAPS组、模型低剂量腺嘌呤(AD)+乙胺丁醇(EMB)组、模型高剂量AD+EMB组及相对应的阳性药别嘌呤醇(Allo)组,连续造模14 d。第3,7,14天分别检测大鼠血尿酸(SUA),尿尿酸(UUA),血肌酐(SCr),尿素氮(BUN),肾损伤分子-1(KIM-1)和中性粒细胞明胶酶相关脂质运载蛋白(NGAL)的水平,在7,14 d收集尿液考察尿量变化,并利用偏光显微镜观察尿残渣中的晶体,造模结束后摘取肾脏称质量并进行病理学检查。结果:模型HX+OAPS组,高剂量AD+EMB组尿量明显减少(P<0.05),除模型YE+OAPS组外,各模型组肾脏指数均明显升高(P<0.05,P<0.01)。模型HX+OAPS组,YE+OAPS组SUA升高较晚(P<0.05),其中,模型HX+OAPS组KIM-1和NGAL从7 d开始明显升高(P<0.05,P<0.01),BUN在14 d明显升高(P<0.05),而模型YE+OAPS组上述指标差异无统计学意义。模型低剂量AD+EMB组,高剂量AD+EMB组3 d时SUA显著升高(P<0.05,P<0.01),其中低剂量AD+EMB组SUA升高具有持续性,BUN,KIM-1,NGAL升高较晚(P<0.05,P<0.01),而高剂量AD+EMB组SUA升高呈一过性,SCr,BUN,KIM-1,NGAL均升高较早且显著高于低剂量AD+EMB组(P<0.01)。除模型YE+OAPS组外,其他模型组肾脏组织中均可见明显的组织形态学异常,其中模型高剂量AD+EMB组的损伤程度最高。结论:4种常用于中药筛选的HUA模型各有特点,其中模型HX+OAPS组,YE+OAPS组的SUA升高较晚,HX+OAPS组伴有轻微肾损伤,YE+OAPS组未发现肾损伤;模型低剂量AD+EMB组造模后SUA迅速升高且持续时间相对较长,同时伴有轻微肾损伤;模型高剂量AD+EMB组SUA升高较早且呈一过性,肾损伤程度颇为严重。考察不同模型的特点及适用情况,同时结合灵敏客观的指标对模型进行评价,有�Objective: To compare the characteristics of four commonly adopted animal models of hyperuricemia(HUA)for traditional Chinese medicine(TCM)screening,so as to choose the adequate model for screening Chinese herbs and herbal compounds capable of lowering the uric acid. Method: Fifty-four male SD rats were randomly divided into nine groups,namely the normal group,hypoxanthine(HX)+ oxonic acid potassium salt(OAPS) model group,yeast extract(YE) + OAPS model group,low-dose adenine(AD) +ethambutol(EMB)model group,high-dose AD + EMB model group,and four positive drug allopurinol(Allo)groups. The modeling lasted for 14 d. The levels of serum uric acid(SUA),urinary uric acid(UUA),serum creatinine(SCr),urea nitrogen(BUN),kidney injury molecule 1(KIM-1),and neutrophil gelatinaseassociated lipocalin(NGAL)were detected on the 3 rd,7 th,and 14 th days. Urine was collected on the 7 th and14 th days to investigate changes in urine volume,and the crystals in the residual urine were observed under a polarizing microscope. After the modeling,the kidney was harvested and weighed,followed by pathological examination. Result: The urine volumes in the HX + OAPS model group and high-dose AD + EMB model group were significantly reduced(P<0.05). The renal indexes of each model group,except for the YE + OAPS model group,were significantly elevated(P<0.05,P<0.01). The increase in SUA of the HX + OAPS model group and YE + OAPS model group started later(P<0.05). The KIM-1 and NGAL levels of the HX + OAPS model group rose significantly from the 7 th day(P<0.05,P<0.01),and the BUN increased significantly on the14 th day(P<0.05). There was no significant difference in the above-mentioned indicators in the YE + OAPS model group. The SUA levels of the low-and high-dose AD + EMB model groups increased significantly on the3 rd day(P<0.05,P<0.01),with a persistent increase found in the low-dose AD + EMB model group. Besides,the increase in BUN,KIM-1,and NGAL occurred later(P<0.05,P<0.01). By contrast,the high-dose AD +EMB model group exhibited a trans

关 键 词：高尿酸血症 中药 动物模型 肾损伤 尿酸盐结晶 

分 类 号：R2-0[医药卫生—中医学] R22