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中华肾病研究电子杂志

中华肾病研究电子杂志 ›› 2018, Vol. 07 ›› Issue (04) : 167 -171. doi: 10.3877/cma.j.issn.2095-3216.2018.04.007

所属专题： 文献；

论著

STAT3抑制剂S3I－201对实验性肾小管间质纤维化的保护作用
梅艳1, 朱凤阁1, 朱晗玉1, 段姝伟1, 洪权1, 马倩1, 蔡广研1, 陈香美1,†()   
  1. 1. 100853　北京，解放军总医院肾脏病科、解放军肾脏病研究所、肾脏疾病国家重点实验室、国家慢性肾病临床医学研究中心
  • 收稿日期:2018-06-23 出版日期:2018-08-28
  • 通信作者: 陈香美
  • 基金资助:
    国家自然科学基金(81330019，81500566)

Protective effects of STAT3 inhibitor S3I-201 in experimental renal tubulointerstitial fibrosis

Yan Mei1, Fengge Zhu1, Hanyu Zhu1, Shuwei Duan1, Quan Hong1, Qian Ma1, Guangyan Cai1, Xiangmei Chen1,†()   

  1. 1. Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China
  • Received:2018-06-23 Published:2018-08-28
  • Corresponding author: Xiangmei Chen
  • About author:
    Corresponding author: Chen Xiangmei, Email:
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梅艳, 朱凤阁, 朱晗玉, 段姝伟, 洪权, 马倩, 蔡广研, 陈香美. STAT3抑制剂S3I－201对实验性肾小管间质纤维化的保护作用[J]. 中华肾病研究电子杂志, 2018, 07(04): 167-171.

Yan Mei, Fengge Zhu, Hanyu Zhu, Shuwei Duan, Quan Hong, Qian Ma, Guangyan Cai, Xiangmei Chen. Protective effects of STAT3 inhibitor S3I-201 in experimental renal tubulointerstitial fibrosis[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2018, 07(04): 167-171.

目的

探讨STAT3抑制剂S3I－201对小鼠实验性肾小管间质纤维化的保护作用。

方法

采用单侧输尿管梗阻手术的方法建立肾小管间质纤维化模型。将实验小鼠随机分为药物假手术组(Sham＋S3I－201)，安慰剂假手术组(Sham＋Vehicle)，药物造模组(UUO＋S3I－201)，安慰剂造模组(UUO＋Vehicle)4组，通过腹腔注射S3I－201溶液(药物)或0.05%DMSO PBS(安慰剂)给药，每天给药一次。造模第7天时留取肾脏标本，用Masson染色和颜色面积测算法评估胶原蛋白沉积的情况。用qRT－PCR法检测肾组织内趋化因子配体16(CXCL16)，白介素－1β(IL－1β)，细胞间黏附分子1(ICAM－1)，转化生长因子－β(TGF－β)，肿瘤坏死因子(TNF－α)的mRNA表达，用免疫组化法染色和免疫印迹法检测PDGFRβ蛋白在梗阻肾脏内的表达。

结果

UUO＋Vehicle小鼠的肾间质胶原蛋白沉积显著高于Sham＋Vehicle组(P<0.05)。UUO＋Vehicle小鼠肾组织CXCL16，IL－1β，ICAM－1，TGF－β，TNF－α的mRNA表达显著高于Sham＋Vehicle组(P<0.05)，UUO＋Vehicle小鼠肾组织血小板来源生长因子受体β(PDGFRβ)蛋白表达显著高于Sham＋Vehicle组(P<0.05)。经过S3I－201治疗7 d后，UUO＋S3I－201小鼠的上述各项指标均显著低于UUO＋Vehicle(P<0.05)。

结论

S3I－201通过抑制多种细胞因子的mRNA表达，以及降低PDGFRβ蛋白的表达，减轻实验性肾小管间质纤维化小鼠的肾间质炎症反应，从而发挥肾脏保护作用。

关键词: 纤维化, 单侧输尿管梗阻, 信号传导与转录激活因子3, S3I－201
Objective

To investigate the protective effects of STAT3 inhibitor S3I-201 in experimental renal tubulointerstitial fibrosis of mice.

Methods

A model of renal tubulointerstitial fibrosis was established by the method of unilateral ureteral obstruction (UUO). The experimental mice were randomly divided into a drug-sham operation group (Sham+ S3I-201), a placebo-sham operation group (Sham+ Vehicle), a drug-model group (UUO+ S3I-201), and a placebo-model group (UUO+ Vehicle). The four groups were administered intraperitoneally with S3I-201 solution (drug) or 0.05% DMSO PBS (placebo), once daily. Kidney specimens were taken on the 7th day of modeling, and collagen deposition was assessed by Masson staining and color area measurement algorithm. The qRT-PCR method was used to detect the mRNA expression of chemokine C-X-C-motif ligand 16 (CXCL16), interleukin-1β (IL-1β), intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α), while immunohistochemical staining and immunoblotting methods were used to detect the protein expression of platelet-derived growth factor receptor β (PDGFRβ) in the obstructed kidneys.

Results

Renal interstitial collagen deposition was significantly higher in the placebo-model group (UUO+ Vehicle) than in the placebo-sham operation group (Sham+ Vehicle) (P<0.05). The mRNA expression of CXCL16, IL-1β, ICAM-1, TGF-β, and TNF-α were also significantly higher in the placebo-model group (UUO+ Vehicle) than in the placebo-sham operation group (Sham+ Vehicle) (P<0.05). The protein expression of PDGFRβ was significantly higher in the placebo-model group (UUO+ Vehicle) than in the placebo-sham operation group (Sham+ Vehicle) (P<0.05). After S3I-201 treatment for 7 days, the above indexes were significantly lower in the drug-model group (UUO+ S3I-201) than in placebo-model group (UUO+ Vehicle).

Conclusion

S3I-201 had a renal protective effect by inhibiting mRNA expression of various cytokines, decreasing protein expression of PDGFRβ, and reducing renal interstitial inflammation in mice with experimental tubulointerstitial fibrosis.

Key words: Fibrosis, Unilateral ureteral obstruction, Signal transducers and activators of transcription, S3I-201
图1 S3I－201治疗单侧输尿管梗阻小鼠后各组肾脏病理改变和胶原蛋白沉积情况
图2 STAT3抑制剂S3I－201治疗后CXCL16，IL－1β，ICAM－1，TGF－β，TNF－α的mRNA转录情况
图3 单侧输尿管梗阻小鼠应用S3I－201后PDGFRβ阳性数量及PDGFRβ蛋白表达情况
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