中文摘要：

目的探讨Janus蛋白酪氨酸激酶．信号转导子和转录激活子（JAK-STAT）通路在小鼠单侧输尿管梗阻（UUO）模型肾间质纤维化过程中的作用。方法选用30只雄性Balb／c小鼠建立小鼠UUO模型（n=24）和假手术小鼠（n=6），术后第1、4、7和14天检测JAK-STAT磷酸化情况。另把18只雄性Balb／c小鼠随机分为假手术组、UUO模型组和治疗组，每组各6只。治疗组在建模前2h开始给予选择性JAK2抑制剂AG490治疗，每天1次；模型组仅注射溶媒。术后第14天处死动物。组织学评估肾小管损伤和肾间质纤维化程度；免疫组化检测肾脏巨噬细胞浸润和α-SMA表达；RT-PCR检测Ⅲ型胶原和单核细胞趋化蛋白（MCP）1mRNA表达：Western印迹检测JAK2和STATl磷酸化。结果JAK2-STATl在UUO模型中被激活，其磷酸化水平与病情、肾小管组织学损害以及肾问质纤维化相一致。AG490能显著抑制JAK2和STATl的磷酸化（P〈0．01）。AG490治疗显著减轻肾小管损害[（21．7±1．7）％比（49．4±1．0）％]和肾间质纤维化（1．0±0．1比2．3±0．2）、α-SMA表达（0．9±0．1比2．1±O.2）和巨噬细胞积聚[（13．3±1．6）细胞／HPF 比（34．4±1．0）细胞／HPF]（均P〈0．01）。AG490治疗显著抑制Ⅲ型胶原和MCP-1mRNA表达。结论JAK-STAT信号通路在肾小管问质炎性反应和纤维化中发挥重要作用。

英文摘要：

Objective To study the role of JAK-STAT singal transduction pathway in the interstitial fibrosis of unilateral ureter obstruction （UUO） mice. Methods Mice UUO model was established and the phosphorylation of JAK-STAT was examined at day 1, 4, 7 and 14 after ligation of the ureter. Mice in the treatment group were treated with daily injection of selective JAK2 inhibitor AG490 starting 2 h before ureter ligation until sacrifice while vehicle alone was given to mice in the model control group. Mice were sacrificed at day 14 after the establishment of model. Renal tubular lesion and interstitial fibrosis were assessed on paraffin section. Immunohistochemistry was used to detect renal macrophage infiltration and α-SMA expression. The expression of collagen Ⅲ and MCP-1 mRNA was measured by RT-PCR. Phosphorylation of JAK2 and STAT1 was examined by Western blotting. Results JAK2-STAT1 signaling transduction pathway was activated in UUO model. The activation of JAK2-STAT1 was closely correlated with the progression of renal injury,tubular histological lesions and interstitial fibrosis.AG490 rteatment significantly inhibited the phosphorylation of JAK2 and STAT1 （P〈0.01）.AG490 treatment also significantly reduced tubular lesions[（21.7±1.7）% vs （49.4±1.0）%] and interstitial fibrosis （1.0±0.1 vs 2.3±0.2）,α-SMA expression （0.9±0.1 vs 2.1±0.2） and macrophage accumulation [（13.3±1.6） cells/HPF vs （34.4±1.0）cells/HPF]（all P〈0.01）.In addition,AG490 significantly inhibited the expression of collagen Ⅲ and MCP-1 mRNA. Conclusion JAK-STAT signaling plays an important role in renal tubulointerstitial inflammation and fibrosis.