川芎嗪对糖尿病肾病大鼠下调HMGB1表达及降低RAGEs作用

Effects of tetramethylpyrazine on the down-regulation of HMGB1 expression and reducing contents of RAGEs in diabetic nephropathy rats

目的:探讨川芎嗪对链脲佐菌素诱导2型糖尿病大鼠肾病的治疗作用及机制。方法:SD大鼠50只,随机分为正常组和模型组。除正常组外,其余大鼠均给予高脂-高糖饲料喂养4周,再给予链脲佐菌素(40 mg/kg,ip),72 h后测定空腹血糖,将血糖值高于16.67 mmol/L的大鼠随机分成4个组,即模型组,二甲双胍阳性组(250 mg/kg),川芎嗪低(80 mg/kg)、高剂量组(160 mg/kg),连续给予相应试药8周。其中正常组和模型组的大鼠均给予同等量蒸馏水灌胃。实验结束时,测定大鼠血糖、尿蛋白、血尿素氮、血肌酐、胰岛素、胰岛素抵抗指数和糖基化终末产物受体(receptor for advanced glycation end-products,RAGEs)含量;免疫组化法测定大鼠肾组织高迁移率族蛋白B1(high mobility group box 1,HMGB1)蛋白表达,光镜下观察肾脏病理学变化。结果:与模型组比较,二甲双胍和高、低剂量川芎嗪给药8周后,均能明显降低大鼠动态空腹血糖(P<0.01),动态尿蛋白总排出量显著降低(P<0.05或P<0.01);二甲双胍及高剂量川芎嗪均能明显降低大鼠肌酐,尿素氮及RAGEs含量(P<0.05或P<0.01);二甲双胍组和高剂量川芎嗪组HMGB1蛋白表达明显低于模型组(P<0.05);肾脏组织病理性损伤明显减轻。结论:川芎嗪对链脲佐菌素诱导2型糖尿病大鼠早期肾病具有保护作用,其机制可能与下调HMGB1表达作用及降低RAGEs作用有关。

AIM：To investigate the therapeutic effects and mechanisms of tetramethylpyrazine（TMP） on streptozocin（STZ）-induced-nephropathy in type 2 diabetic rats.METHODS：Fifty SD rats were randomly divided into control group（n=10）and model group（n=40）.All model rats were fed with high-fat diet for 4 weeks and then injected with streptozotocin（STZ,40 mg/kg,ip）.Fasting blood glucose（FBG） was measured by One-Touch glucometer after 72 h.Rats with fasting blood glucose above 16.67 mmol/L were then randomly divided into four groups：model,metformin（250 mg/kg）,low-TMP（80 mg/kg） and high-TMP（160 mg/kg）groups,and the later three received respective drug for 8 weeks,while control and model groups were given equal amount of distilled water by intragastric administration.At the end of the experiment,blood glucose,urine protein,blood urea nitrogen,creatinine,insulin,HOMA-IRI and receptor for advanced glycationend-products（RAGEs） were measured.The expression of high mobility group box 1（HMGB1） in kidney tissue of rats was determined by immunohistochemistry.Pathological damages of kidney were observed under light microscope.RESULTS：After 8 weeks ＇ administration,compared with the model group,metformin group,low-TMP and high-TMP group showed significant decrease in the dynamic fasting blood glucose（P〈0.01） and urinary protein excretion of total dynamic（P〈0.05 or P〈0.01）;Metformin and high-TMP can significantly reduce the level of Cr,BUN and RAGEs;the protein expressions of HMGB1 in metformin group and high-TMP group were significantly lower than that in model group（P〈0.05）;pathological damages of kidney tissue were significantly reduced.CONCLUSION：TMP exhibited protective effect on STZ induced nephropathy in type 2 diabetic rats and its mechanism may be related to the down-regulation of HGMB1 expression and reducing contents of RAGEs.