紫草素通过Smad3/Erbb4-IR轴对肾脏纤维化的抑制作用研究  

Protective effect of shikonin on renal fibrosis via Smad3/long-chain non-coding Erbb4-IR axis

作　　者：廖媛 李健春 谭睿陟 张宇韦 王丽 樊均明 LIAO Yuan;LI Jian-chun;TAN Rui-zhi;ZHANG Yu-wei;WANG Li;FAN Jun-ming(Dept of Nephrology,the Affiliated Hospital of Traditional ChineseMedicine,Southwest Medical University,Luzhou Sichuan 646000,China;Research Center of Integrated Chinese and Western Medicine,the Affiliated Hospital of Traditional Chinese Medicine,Southwest Medical University,Luzhou Sichuan 646000,China;Chengdu Medical College,Chengdu 610000,China)

机构地区：[1]西南医科大学附属中医医院肾病内科,四川泸州646000 [2]西南医科大学附属中医医院中西医结合研究中心,四川泸州646000 [3]成都医学院,四川成都610000

出　　处：《中国药理学通报》2019年第12期1699-1704,共6页Chinese Pharmacological Bulletin

基　　金：四川省医学重点实验室建设项目(川卫办发[2018]53号);泸州市科技计划项目[2018LZXNYD-PT03,2016-S-68(4/8)]

摘　　要：目的研究紫草素对单侧输尿管梗阻性肾病诱导的小鼠纤维化模型的治疗作用和潜在调控机制。方法选取C57BL/6雄性小鼠30只,8周龄,体质量(20~22)g,随机分为假手术组、UUO组、紫草素低和高剂量组、厄贝沙坦组,紫草素组于术前1 h给予紫草素第1d的灌胃,连续灌胃10 d后处死小鼠,收集血清,HE和PAS观察肾脏病理,MASSON检测肾间质纤维化,IHC检测α-SMA,Western blot检测肾组织中纤维化指标和p-Smad3、Smad7的表达,RT-PCR检测TGF-β和长链非编码Erbb4-IR。结果与模型组相比,紫草素治疗后,肾功改善,病理染色显示肾小管损伤明显改善,纤维化减少;免疫印迹结果显示紫草素能够抑制TGF-β/Smad信号通路中关键蛋白Smad3活化,上调Smad7表达,而TGF-β和长链非编码Erbb4-IR的基因表达均呈现剂量依赖性下降。结论紫草素可有效减轻肾脏纤维化,其机制可能与调节Smad3/Erbb4-IR轴相关。Aim To investigate the therapeutic effect of shikonin on unilateral ureteral obstructive nephropathy(UUO)-induced CKD mouse fibrosis model and the potential regulatory mechanism.Methods Thirty C57BL/6 mice(8 weeks old,weighing 20-22 g)were randomly divided into sham group,UUO model group,low dose shikonin group(5 mg·kg^-1),high dose shikonin group(20 mg·kg^-1)and irbesartan group(20 mg·kg^-1).Mice in shikonin groups were given the first drug intragastrically for one day before operation,and then were sacrificed for 10 days after continuous gavage.Creatine and urea nitrogen were detected,renal pathology was observed by HE and PAS,renal interstitial fibrosis was detected by MASSON,α-SMA was detected by IHC,andα-SMA,FN,p-Smad3,Smad3 and Smad7 expression in renal tissues were detected by Western blot.TGF-βand long-chain non-coding Erbb4-IR were detected by RT-PCR.Results Compared with model group,serum creatinine and urea nitrogen significantly decreased after treatment with shikonin.HE showed marked improvement in renal tubular injury.PAS and MASSON staining showed decreased glycogen deposition and fibrosis.Western blot showed shikonin inhibited the activation of the key protein Smad3 in the TGF-β/Smad signaling pathway and up-regulated the expression of Smad7,while the expression of TGF-βand long-chain non-encoding Erbb4-IR decreased in a dose-dependent manner.Conclusions Shikonin can effectively alleviate renal fibrosis,and its mechanism may be related to the regulation of Smad3/long-chain non-coding Erbb4-IR axis.

关 键 词：紫草素 SMAD3 Erbb4-IR 肾纤维化 lncRNA TGF-β 

分 类 号：R-332[医药卫生] R284.1