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首页 > 过刊浏览>2023年第31卷第1期 >10-19. DOI:10. 3969 / j.issn.1005-4847. 2023. 01. 002
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基于TGF-β1/ Smad 信号通路初步探讨虎杖醇提物对腺嘌呤诱导小鼠肾间质纤维化的改善作用
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1. 浙江中医药大学 药学院,杭州 310053;2. 杭州医学院 安全性评价研究中心,杭州 310053;3. 浙江省药物安全性评价技术研究重点实验室,杭州医学院,杭州 310053


Ethanolic extract of Polygonum cuspidatum attenuates renal fibrosis in a mouse model of adenine-induced renal injury through inhibiting TGF-β1/ Smad signaling
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1. School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China. 2. Center for Drug Safety Evaluation, Hangzhou Medical College, Hangzhou 310053. 3. Key Laboratory of Drug Safety Evaluation and Research of Zhejiang Province, Hangzhou Medical College, Hangzhou 310053

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    摘要:

    目的 研究虎杖醇提物(ethanolic extract of Polygonum cuspidatum,PCE)对小鼠肾间质纤维化的保护作用及其潜在分子机制。 方法 将50 只雄性C57BL/6N 小鼠随机分为5 组(n=10):正常对照组、模型组、虎杖醇提物低、中、高(75、150、300 mg/ kg)剂量组。除正常对照组外,其他各组灌胃腺嘌呤构建肾间质纤维化模型,虎杖醇提物低、中、高剂量组同时灌胃给予不同剂量的虎杖醇提物混悬液。各组经灌胃给药42 d 后用生化试剂盒测定血清肌酐(serum creatinine, Scr)和尿素氮(blood urea nitrogen, BUN)水平,通过苏木精伊红染色和Masson 三色染色分别观察小鼠肾组织病理学变化及胶原沉积情况,采用Western Blot 法检测小鼠肾组织中转化生长因子-β1(transforming growth factor-β1,TGF-β1)、Smad6、α 平滑肌肌动蛋白(α-smooth muscle actin, α-SMA)、I 型胶原蛋白(Collagen I)的表达情况。 结果 与正常对照组比较,模型组小鼠BUN、Scr 水平显著增高(P< 0. 01)。肾组织病理学HE 染色可见肾小管结构破坏,炎细胞浸润肾间质,完整的健存肾单位明显减少;Masson 染色可见胶原纤维蓝色阳性染色面积明显增多。肾组织TGF-β1 的表达明显增多(P< 0. 01),而TGF-β/ Smad 通路的负调节因子Smad6的表达显著下调(P< 0. 01)。上皮-间充质转化(epithelial-mesenchymal transformation, EMT) 标志蛋白之一α-SMA、细胞外基质(extracellular matrix,ECM)蛋白之一Collagen I 的表达明显增加(P< 0. 01)。与模型组相比,虎杖醇提物各给药组BUN、Scr 水平以及肾组织TGF-β1、α-SMA 及Collagen I 的蛋白表达水平呈剂量依赖性降低,Smad6 的表达水平呈剂量依赖性升高。肾组织的病理改变及纤维沉积面积均有不同程度的改善。 结论 虎杖醇提物能减轻腺嘌呤诱导的小鼠肾功能损伤,改善肾间质纤维化,其机制与干预TGF-β1/ Smad 信号通路,抑制EMT及ECM 蛋白沉积有关。

    Abstract:

    Objective This study aimed to test the efficacy of an ethanolic extract of Polygonum cuspidatum(PCE) against adenine-induced renal interstitial fibrosis (RIF) in C57BL/6N mice and reveal its underlying molecular mechanisms of action. Methods An RIF model was induced by gavaging C57BL/6N mice with adenine. Fifty male C57BL/6N mice were randomly divided into five groups (n=10 per group): normal control group, model group, PCE-L, PCE-M and PCE-H (75, 150, 300 mg/ kg, respectively) groups. After treatment for 42 consecutive days, serum creatinine (Scr) and blood urea nitrogen (BUN) levels were measured with commercially purchased kits. Histopathological changes to the kidneys were assessed by HE and Masson staining. The protein expression levels of TGF-β1, Smad6, α-SMA, and type I collagen (Collagen I) in kidney tissue were detected by Western Blot. Results Compared with the normal control group, the model group had significantly increased BUN and Scr (P<0. 01). The protein expression level of TGF-β1 was significantly increased (P< 0. 01), while Smad6, a negative regulator of the TGF-β/ Smad pathway, was significantly downregulated (P< 0. 01). The expression of the epithelial-mesenchymal transformation (EMT) marker protein α-SMA and the extracellular matrix (ECM) protein Collagen I were significantly increased (P< 0. 01). Compared with the model group, the drug intervention groups showed decreased levels of BUN and Scr; declining protein expression levels of TGF-β1, α-SMA and Collagen I; increased levels of Smad6 protein; and the alleviation of pathological changes. Conclusions PCE treatment attenuated adenine-induced renal impairment and ameliorated renal interstitial fibrosis in mice. The mechanism of action may be related to changes to the TGF-β1/ Smad signaling pathway and the suppression of EMT and ECM protein deposition.

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段艳华,陈云祥,郑高利,温磊,陈浩,张丽丽,秦荔,王佳虹,刘芳,夏道宗,张立将.基于TGF-β1/ Smad 信号通路初步探讨虎杖醇提物对腺嘌呤诱导小鼠肾间质纤维化的改善作用[J].中国实验动物学报,2023,31(1):10~19.

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  • 收稿日期:2022-09-26
  • 在线发布日期: 2023-10-17
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