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江丽红, 姚强, 罗晨, 陆华冠, 王宇红, 刘建军.基于TGF-β1/Smad信号通路探讨天芙止眩方改善自发性高血压大鼠肾纤维化的作用机制[J].湖南中医药大学学报英文版,2025,45(4):608-616.[Click to copy
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| 基于TGF-β1/Smad信号通路探讨天芙止眩方改善自发性高血压大鼠肾纤维化的作用机制 |
| 江丽红,姚强,罗晨,陆华冠,王宇红,刘建军 |
| (湖南中医药大学科技创新中心, 湖南 长沙 410208) |
| 摘要: |
| 目的 基于转化生长因子-β1（TGF-β1）/Smad信号通路探讨天芙止眩方对自发性高血压（SHR）大鼠肾纤维化和炎症的改善作用。方法 将40只SHR大鼠随机分为5组：模型组、厄贝沙坦组（13.5 mg/kg）及天芙止眩方高（5.94 g/kg）、中（2.97 g/kg）、低（1.49 g/kg）剂量组，每组8只；另取8只WKY大鼠作为正常组。模型组和正常组给予等体积蒸馏水。各组均连续灌胃给药11周，每天1次。分别在第1、3、5、7、9、11周测量大鼠尾动脉收缩压及舒张压。实验结束后，生化分析仪检测血清中尿素氮（BUN）、肌酐（Scr）含量；ELISA法检测血清中血管紧张素Ⅱ（AngⅡ）、白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）的含量；HE、Masson及天狼星红染色检测肾组织病理变化和胶原纤维沉积；免疫组织化学染色法检测肾组织Ⅰ型胶原（CollagenⅠ）、 Ⅲ型胶原（CollagenⅢ）、TGF-β1、CD68蛋白表达；Western blot法检测肾组织CD68、TGF-β1蛋白表达及磷酸化细胞信号转导分子2/3（p-Smad2/3）和细胞信号转导分子2/3（Smad2/3）的蛋白比值；RT-qPCR检测AngⅡ、TGF-β1、CD68的mRNA表达。结果 与正常组比较，模型组 SHR大鼠第1、3、5、7、9、11周收缩压和舒张压均升高（P＜0.001）；血清BUN、Scr、AngⅡ、IL-1β、TNF-α水平升高（P＜0.01，P＜0.001）；肾组织出现病理损伤和炎性浸润，并形成明显的纤维化，CollagenⅠ和CollagenⅢ的蛋白表达升高（P＜0.001），CD68、TGF-β1、p-Smad2/3和Smad2/3的蛋白比值及AngⅡ、TGF-β1、CD68的mRNA水平均增高（P＜0.01，P＜0.001）。与模型组比较，厄贝沙坦组及天芙止眩方高、中剂量组第3、5、7、9、11周收缩压及舒张压均降低（P＜0.01），天芙止眩方低剂量组第5、7、9、11周收缩压及舒张压下降（P＜0.05，P＜0.01）；血清BUN、Scr、AngⅡ、IL-1β、TNF-α水平降低（P＜0.05，P＜0.01）；肾组织病理损伤明显改善，炎症浸润及纤维化减少，CollagenⅠ、CollagenⅢ的蛋白表达降低（P＜0.05或P＜0.01），CD68、TGF-β1、p-Smad2/3和Smad2/3的蛋白比值及AngⅡ、TGF-β1、CD68 的mRNA水平均降低（P＜0.05，P＜0.01）。结论 天芙止眩方治疗能有效降低SHR大鼠血压并改善高血压引起的肾纤维化，其机制可能与减少组织炎症，抑制TGF-β1/Smad信号通路有关。 |
| 关键词: 高血压 天芙止眩方 肾纤维化 巨噬细胞 TGF-β1/Smad信号通路 |
| DOI：10.3969/j.issn.1674-070X.2025.04.004 |
| Received:July 18, 2024 |
| 基金项目:湖南省自然科学基金项目（2024JJ8158）；湖南中医药大学科研创新基金项目（2023BKS146）；湖南中医药大学研究生创新课题（2024CX078）。 |
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| Mechanism of Tianfu Zhixuan Formula in alleviating renal fibrosis in spontaneously hypertensive rats based on the TGF-β1/Smad signaling pathway |
| JIANG Lihong, YAO Qiang, LUO Chen, LU Huaguan, WANG Yuhong, LIU Jianjun |
| (Science and Technology Innovation Center, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China) |
| Abstract: |
| Objective To explore the alleviative effects of Tianfu Zhixuan Formula (TFZXF) on renal fibrosis and inflammation in spontaneously hypertensive rats (SHR) based on the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. Methods Forty SHR rats were randomly divided into five groups: a model group, an irbesartan group (13.5 mg/kg), and high- (5.94 g/kg), medium- (2.97 g/kg), and low- (1.49 g/kg) dose TFZXF groups, with eight rats in each group. Another eight WKY rats were used as the normal group. The model groups and the normal group were given an equal volume of distilled water. All groups were administered by gavage for 11 consecutive weeks, once a day. The systolic and diastolic blood pressures of the rats' tail artery were measured at weeks 1, 3, 5, 7, 9, and 11. After the experiment, the levels of blood urea nitrogen (BUN) and creatinine (Scr) in the serum were measured by the biochemical analyzer. The levels of angiotensinⅡ (AngⅡ), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in the serum were measured by ELISA. The pathological changes and collagen fiber deposition in renal tissue were measured by HE, Masson, and Sirius red staining. The expressions of typeⅠ collagen (CollagenⅠ), typeⅢ collagen (CollagenⅢ), TGF-β1, and CD68 proteins in renal tissue were measured by immunohistochemical staining. The protein expressions of CD68 and TGF-β1 in renal tissue, as well as the protein ratios of phosphorylated cellular signal transduction molecules Smad2/3 (p-Smad2/3) to cellular signal transduction molecules 2/3 (Smad2/3), were measured by Western blot. And the mRNA expressions of AngⅡ, TGF-β1, and CD68 were measured by RT-qPCR. Results Compared with the control group, the SHR rats in the model group showed increased systolic and diastolic blood pressure at weeks 1, 3, 5, 7, 9, and 11 (P＜0.001). The levels of serum BUN, Scr, AngⅡ, IL-1β, and TNF-α were higher (P＜0.01, P＜0.001). The renal tissue in the model group exhibited pathological damage, inflammatory infiltration, and significant fibrosis. The protein expressions of CollagenⅠ and CollagenⅢ increased (P＜0.001). The protein expression levels of CD68 and TGF-β1, the protein ratio of p-Smad2/3 and Smad2/3, as well as the mRNA levels of AngⅡ, TGF-β1, and CD68, were all higher (P＜0.01, P＜0.001). Compared with the model group, the irbesartan group and the high- and medium-dose TFZXF groups showed decreased systolic and diastolic blood pressure at weeks 3, 5, 7, 9, and 11 (P＜0.01). The low-dose TFZXF group showed decreased systolic and diastolic blood pressure at weeks 5, 7, 9, and 11 (P＜0.05, P＜0.01). The levels of serum BUN, Scr, AngⅡ, IL-1β, and TNF-α decreased (P＜0.05, P＜0.01). The pathological damage in the renal tissue was significantly relieved, with reduced inflammatory infiltration and fibrosis. The protein expressions of CollagenⅠ and CollagenⅢ decreased (P＜0.05, P＜0.01). The protein expression levels of CD68 and TGF-β1, the protein ratio of p-Smad2/3 and Smad2/3, as well as the mRNA levels of AngⅡ, TGF-β1, and CD68, were all lower (P＜0.05, P＜0.01). Conclusion Treatment with TFZXF can effectively reduce blood pressure and alleviate hypertension-induced renal fibrosis in SHR rats. The mechanism may be related to reducing tissue inflammation and inhibiting the TGF-β1/Smad signaling pathway. |
| Key words: hypertension Tianfu Zhixuan Formula renal fibrosis macrophages TGF-β1/Smad signaling pathway |
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