糖蛋白 130 小分子抑制剂 SC144 对单侧输尿管梗阻小鼠肾间质纤维化的影响
Effect of GP130 small molecular inhibitor SC144 on renal interstitial fibrosis in mice with unilateral ureteral obstruction

目的 · 动态观察糖蛋白 130 小分子抑制剂 SC144 对单侧输尿管梗阻（unilateral ureteral obstruction，UUO）小鼠肾组织细胞外基质堆积和 Janus 蛋白酪氨酸激酶 2（Janus kinase 2，JAK2）/ 信号转导与转录激活因子 3（signal transduction and activator of transcription 3，STAT3）信号转导通路（简称 JAK2/STAT3 信号通路）的影响，探讨 SC144 防治肾间质纤维化的可能机制。方法 · 将 18 只雌性 BALB/c 小鼠分为 3 组：假手术组、模型对照组和 SC144 干预组。于造模后第 14 日，用苏木精 - 伊红染色（hematoxylineosin staining，H-E 染色）、Masson 染色观察肾组织学形态改变，免疫组织化学检测肾脏巨噬细胞浸润和 α- 平滑肌肌动蛋白（α-smooth muscle actin，α-SMA）表达，real-time PCR 检测 I 型 /IV 型胶原、单核细胞趋化蛋白 -1（monocyte chemoattractant protein-1， MCP-1）、转化生长因子 -β（transforming growth factor-β，TGF-β）的 mRNA 水平，Western blotting 检测肾组织 JAK2、STAT3 的表达和磷酸化水平。结果 · SC144 干预组肾小管间质损伤程度有明显减轻趋势（H-E 染色，P=0.052；Masson 染色，P=0.063）；肾组织内纤维化指标 α-SMA、I 型 /IV 型胶原和 TGF-β 的 mRNA 表达下降，与模型对照组相比差异具有统计学意义（均 P<0.05）。纤维化信号通路的 JAK2 和 STAT3 的磷酸化水平较模型对照组下降（均 P<0.05）。结论 · 在小鼠 UUO 模型中，小分子抑制剂 SC144 能抑制 α-SMA 的活化及 STAT3 的磷酸化，通过 JAK2/STAT3 信号通路减轻肾小管上皮间质转化、减少细胞外基质表达，具有延缓 UUO 小鼠肾间质纤维化进程的作用。
：Objective · To investigate the effect of glycoprotein 130 (GP130) inhibitor SC144 on extracellular matrix accumulation and JAK2/STAT3 signaling pathway in unilateral ureteral obstruction (UUO) mouse model, and explore its mechanism. Methods · Eighteen female BALB/c mice were randomly divided into 3 groups i.e. sham group, UUO group and SC144 group. All mice were sacrificed at day 14 and kidneys were harvested for further analysis. The changes of renal tissue morphology and pathology were observed by H-E and Masson staining. The expression of α-smooth muscle actin (α-SMA) and infiltration of macrophage cells were assayed by immunohistochemical staining. The levels of collagen-I, collagen-IV, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-β (TGF-β) mRNA were analyzed by real-time PCR. The activation of JAK2 and STAT3 was measured by Western blotting. Results · There was a trend toward decreased renal tubular lesion and renal interstitial fibrosis in SC144 group (H-E, P=0.052; Masson, P=0.063). SC144 significantly inhibited the levels of α-SMA, type I/type IV collagen and TGF-β mRNA (all P<0.05). Compared with UUO group, the phosphorylation levels of JAK2 and STAT3 were significantly decreased in SC144 group (both P<0.05). Conclusion · The treatment of UUO mouse model with SC144 can inhibit the activation of α-SMA, attenuate the phosphorylation of STAT3, reduce extracellular matrix protein deposition following injury and renal tubular epithelial-mesenchymal transition (EMT) via JAK2/STAT3 signaling pathway, indicating its potential in attenuating interstitial fibrosis in obstructive nephropathy