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目的建立关木通所含马兜铃酸(AA)致大鼠急性肾小管坏死(ATN)实验动物模型,并观察和比较川芎嗪、泼尼松和贝那普利对大鼠肾小管的保护作用。方法将雄性SD大鼠随机分为6组,每组12只。正常组予蒸馏水3 ml／d灌胃;模型组、泼尼松组、贝那普利组、川芎嗪Ⅰ组和川芎嗪Ⅱ组均先予关木通水煎剂(含生药2 g／ml、AA 0．54 mg／ml、AA-I 0．46 mg／ml) 5 g·kg-1·d-1灌胃60 d,再予10 g·kg-1·d-1灌胃30 d。灌关木通2 h后,正常组与模型组予生理盐水灌胃,其余4组分别予泼尼松5 mg·kg-1·d-1、贝那普利1．7 mg·kg-1·d-1、川芎嗪50 mg·kg-1·d-1和川芎嗪150 mg·kg-1·d-1灌胃。于90 d后进行肾组织病理检查。结果正常组为正常肾组织。模型组光镜可见近曲肾小管上皮细胞成片状空泡变性,刷状缘紊乱、消失,管腔内可见脱落的上皮细胞,肾小管基膜(TBM)裸露、部分断裂、个别增厚及萎缩;肾间质轻度水肿、多灶性炎细胞浸润;肾小球系膜细胞局灶节段性轻、中度增生和系膜基质轻度增多;部分小叶间动脉管壁增厚。其余4组与模型组比较,病变均明显减轻,表现为近曲肾小管上皮细胞空泡变性明显减少,少部分刷状缘紊乱、消失,个别管腔内可见脱落的上皮细胞,个别TBM断裂及增厚减轻;肾间质炎细胞减少或消失。模型组电镜可见近曲小管上皮细胞空泡变性和脂肪变性,线粒体肿胀,细胞器减少,细胞核碎裂,细胞凋亡;间质中可见炎细胞浸润(吞噬细胞与淋巴细胞)和淋巴细胞浸入到上皮细胞中;小叶间动脉管壁增厚、管腔狭窄。其余4组与模型组比较,近曲小管上皮细胞轻度空泡变性、个别线粒体肿胀,个别细胞核轻度固缩、大部分正常;间质中可见少量吞噬细胞和淋巴细胞。其中以川芎嗪Ⅱ组和泼尼松组病变减轻尤为显著。结论(1)模型组光镜和电镜结果主要表现为ATN,表明成功建立了大鼠ATN实验动物模型;(2)川芎嗪、泼尼松和贝那普利对AA致大鼠ATN均具有保护作用,且以川芎嗪和泼尼松的药效尤为明显。
Objective To establish an animal model of acute tubular necrosis (ATN) caused by aristolochic acid (AA) in Guanmu Tong and to observe and compare the protective effect of ligustrazine, prednisone and benazepril on rat renal tubules. Methods Male Sprague-Dawley rats were randomly divided into 6 groups with 12 rats in each group. The normal group was treated with distilled water 3 ml / d. The model group, the prednisone group, the benazepril group, the ligustrazine group Ⅰ and the ligustrazine Ⅱ group were given Guan Mu Tong decoction (containing crude drug 2 g / ml, AA 0.54 mg / ml and AA-I 0.46 mg / ml) for 60 days, then gavaged with 10 g · kg-1 · d-1 for 30 days. After 2 hours of administration of Guan Mu Tong, normal saline and normal saline were given to the model group, while the other 4 groups were given prednisone 5 mg · kg-1 · d-1, benazepril 1.7 mg · kg-1 · d -1, ligustrazine 50 mg · kg-1 · d-1 and ligustrazine 150 mg · kg-1 · d-1. Renal histopathology was performed 90 days later. Results The normal group was normal kidney tissue. In the model group, proximal tubular epithelial cells were observed as vacuolar degeneration, disorganized brush edge, disappeared, epithelial cells shedding in the lumen, bare tuber basement membrane (TBM), partial rupture, individual thickening and Atrophy; slight interstitial edema, multifocal inflammatory cell infiltration; focal segmental glomerular mesangial cells mild, moderate hyperplasia and mild increase in mesangial matrix; part of the interlobular artery wall thickening. The remaining 4 groups compared with the model group, lesions were significantly reduced, the performance of proximal tubule epithelial cells vacuolar degeneration significantly reduced, a small part of the brush edge disorder, disappeared, the individual shed visible epithelial cells, individual TBM rupture and Thickening reduced; interstitial inflammation cells decreased or disappeared. Electron microscope showed that the proximal tubule epithelial cells were vacuolar degeneration and steatosis, mitochondria were swollen, organelles were reduced, nuclear fragmentation and apoptosis were observed in the model group. Inflammatory cells infiltration (phagocytes and lymphocytes) and lymphocytes were infiltrated into the epithelium Cells; lobular artery wall thickening, stenosis. The remaining four groups compared with the model group, proximal tubule epithelial cells mild vacuolar degeneration, individual mitochondria swelling, individual nuclei slightly condensed, most of the normal; a small amount of phagocytic cells and lymphocytes can be seen. Among them, ligustrazine Ⅱ group and prednisone group lessened lesions were particularly significant. Conclusions (1) The results of light and electron microscopy in model group were mainly ATN, which indicated that ATN experimental animal model was established successfully. (2) Tetramethylpyrazine, prednisone and benazepril had protective effects on ATN induced by AT in rats Role, and the efficacy of ligustrazine and prednisone is particularly evident.