苓术菟丝子丸抑制IKKB/NF-kB/MCP-1通路减少阿霉素诱导的大鼠肾性蛋白尿
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1.西南医科大学中西医结合学院,四川泸州646000;2.西南医科大学附属中医医院内分泌科,四川泸州646000;3.西南医科大学附属中医医院肾病科,四川泸州646000

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Effects of Ling Zhu Tusizi Pills in inhibiting the I-κB kinase β/ nuclear factor-κB/ monocyte chemoattractant protein-1 signaling pathway to reduce adriamycin-induced proteinuria in rats
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1. College of Integrated Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou 646000,China. 2. Department of Endocrinology, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000. 3. Department of Nephrology, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000

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    摘要:

    目的 探讨苓术菟丝子丸对阿霉素肾病蛋白尿的影响及机制。 方法 将 36 只雄性 SD 大鼠纳入实验。 随机分为 6 组(6 只/ 组)。包括空白、模型组和 PDTC(NF-κB 抑制剂)组(100 mg / ( kg·d)),以及苓术菟丝子丸低、中、高剂量组(14、28、56 g / (kg·d))。 除空白组外的大鼠均用阿霉素造成肾病模型。造模成功后,连续用药6 周。记录一般生命体征;收集检测 24 h 尿蛋白,血浆白蛋白(Alb)、血肌酐( Scr)、尿素氮(BUN)和 C 反应蛋白(CRP);HE、Masson、PAS 染色,透射电镜观察肾病理形态变化;ELISA 检测血清 IL-6、TNF-α 水平;Western Blot 检测IKKβ/ NF-κB/ MCP-1 通路相关蛋白。 结果 模型组大鼠生存状态差。 Alb 降低,24 h 尿蛋白升高。 肾小管广泛肿胀,肾小球足突融合;大量纤维沉积,基底膜增厚。血清 IL-6、TNF-α 和 CRP 升高;肾 p-IKKβ、p-NF-κB、MCP-1 表达水平,及 p-IKKβ/ IKKβ、p-NF-κB/ NF-κB 比值升高,nephrin、podocin 表达减少(P < 0. 05)。 给药组除高剂量组外,大鼠一般状况良好。体重升高,24 h 尿蛋白降低,Alb 升高。肾小管肿胀减轻,肾小球足突融合改善。肾小管、小球纤维化减少,基底膜无增厚。血清 IL-6、TNF-α 和 CRP 降低;肾 p-IKKβ、p-NF-κB、MCP-1 表达水平,及 p-IKKβ/ IKKβ、p-NF-κB/ NF-κB 比值减少,nephrin、podocin 表达增多(P< 0. 05)。 结论 苓术菟丝子丸减少阿霉素肾病大鼠 24 h尿蛋白,降低血清炎性因子,其作用机制可能与抑制 IKKβ/ NF-κB/ MCP-1 信号通路有关。

    Abstract:

    Objective To examine the potential mechanism of Ling Zhu Tusizi Pills in a rat model of adriamycininduced proteinuria. Methods Thirty-six specific-pathogen-free male SD rats were divided randomly into six groups (n= 6 rats per group), including blank, model, low-dose Ling Zhu Tusizi (14 g / (kg·d)), medium-dose Ling Zhu Tusizi (28g / (kg·d)), high-dose Ling Zhu Tusizi ( 56 g / ( kg·d)), and pyrrolidine dithiocarbamate ( PDTC; nuclear factor-κB inhibitor; 100 mg / (kg·d)) groups. The last five groups also received two injections of adriamycin into the tail vein to develop the nephropathy model, with one dose of 4 mg / kg and another dose of 2 mg / kg given 1 week apart. After successful establishment of the model, Ling Zhu Tusizi Pills were administered for 6 weeks. We examined general vital signs and body weights of the rats, as well as 24 h urine protein, plasma albumin, serum creatinine, blood urea nitrogen, and C-reactive protein. Morphological alterations of the renal tubules and glomeruli, renal fibrosis and basement membrane thickness were observed by hematoxylin and eosin, Masson, and periodic-acid Schiff staining. Modification of the foot process in glomerular podocytes was observed by transmission electron microscopy. Serum levels of pro-inflammatory molecules including interleukin (IL)-6 and tumor necrosis factor (TNF)-α were detected by enzyme-linked immunosorbent assay. I-κB kinase β( IKKβ) / nuclear factor (NF)-κB/ monocyte chemoattractant protein-1 ( MCP-1) pathway-related proteins and nephrin and podocin proteins were detected by Western Blot. Results General health was poorer in the model group compared with the control group, as evidenced by body weight loss, increased 24 h urine protein, and decreased albumin. Renal tubule enlargement, disorganized glomerular visceral cell arrangement, diffuse foot process fusion, podocyte death,extensive fiber deposition, and basement membrane thickening were also noted in the model group. Serum levels of the proinflammatory markers IL-6, TNF-α and CRP were increased, renal-tissue phosphorylated (p)-IKKβ, p-NF-κB and MCP- 1 protein expression levels and the p-IKKβ/ IKKβ and p-NF-κB/ NF-κB ratios were increased, while nephrin and podocin expression levels were decreased ( P< 0. 05 ) in model compared with control rats. Rats in each treatment group experienced variable degrees of symptom relief compared with the model group, with medium-dose Ling Zhu Tusizi Pills having the best therapeutic effect. Rats in this group were generally healthy, with increased body weight and albumin and decreased 24 h urine protein. There were also notable reductions in fibrosis and renal tubule edema, a smooth arrangement of cells in the glomerular visceral layer, enhanced foot process fusion, and no thickening of the basement membrane. Serum levels of IL-6, TNF-α, and CRP were decreased, nephrin and podocin expression were increased, and p-IKKβ, p-NF-κB,MCP-1, p-IKKβ/ IKKβ and p-NF-κB/ NF-κB expression were all significantly decreased in renal tissues in this group (P<0. 05). Conclusions Ling Zhu Tusizi Pills reduced 24 h urine protein and serum pro-inflammatory markers in rats with adriamycin-induced nephropathy, possibly via inhibition of the IKKβ/ NF-κB/ MCP-1 signaling pathway.

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龙雯,明瑶,李茗西,沈宏春.苓术菟丝子丸抑制IKKB/NF-kB/MCP-1通路减少阿霉素诱导的大鼠肾性蛋白尿[J].中国实验动物学报,2022,30(7):909~917.

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  • 收稿日期:2022-06-06
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  • 在线发布日期: 2023-03-10
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