CCR2抑制剂延缓输尿管结扎小鼠肾纤维化

Chemokine receptor 2 inhibitor alleviates renal interstitial fibrosis in unilateral ureteral obstruction mouse model

目的探究趋化因子受体2(CCR2)抑制剂(RS504393)在小鼠肾纤维化中的作用及其机制。方法将小鼠随机分为假手术组(sham组,单侧输尿管分离术)、UUO模型组(单侧输尿管结扎术)和给药组(UUO+RS504393,术前3天开始灌胃给予RS504393 25 mg/kg,早晚各1次,连续17 d);用Masson染色和HE染色观察肾脏纤维化程度和炎性细胞变化;流式细胞计量术分析各组小鼠肾脏CCR2及CD11b^+Ly6C^+单核细胞的比例。结果 UUO模型组肾间质炎性细胞数量较假手术组明显增多(P<0.05),给药组炎性细胞数量较模型组显著减少(P<0.05);UUO模型组肾脏胶原蛋白沉积面积较假手术组显著增加(P<0.05),给药组胶原沉积面积较模型组明显减少(P<0.05);UUO模型组肾脏CCR2比例较假手术组显著增多(P<0.05),给药组CCR2比例较模型组减少(P<0.05);UUO模型组肾间质CD11b^+Ly6C^+单核细胞群比例较假手术组明显增加(P<0.05),给药组CD11b^+Ly6C^+单核细胞群比例较模型组明显减少(P<0.05)。结论 CCR2抑制剂RS504393可减少CD11b^+Ly6C^+单核细胞浸润延缓肾脏纤维化。

Objective To investigate the role of chemokine receptor 2(CCR2) inhibitor RS504393 in alleviating renal interstitial fibrosis and the underlying mechanisms in unilateral ureteral obstruction mouse model. MethodsMice were randomly divided into three groups: sham group,model group and administration group. The unilateral ureter separation was performed in mice of the sham group, and mice in the other two groups underwent unilateral ureteral obstruction(UUO) to induce renal interstitial fibrosis. Three days before UUO, the mice in the administration group were administered with RS504393 orally twice a day at a dose of 25 mg/kg for 17 consecutive days. Masson and HE staining were used to determine the degree of renal fibrosis and the inflammatory cells infiltration. Flow cytometry analysis was used to determine the proportion of CCR2 and CD11 b^+Ly6 C^+ monocytes. ResultsCompared with sham group, the degree of renal fibrosis was significantly increased in model group(P<0.05). Renal fibrosis was alleviated in the administration group compared to model group(P<0.05);Compared with sham group,the infiltration of inflammatory cells was increased in model group( P<0. 05),compared with model group,the infiltration of inflammatory cells reduced in the administration group( P<0. 05);The percentage of CCR2 and CD11b^+Ly6C^+ monocytes was increased in model group as compared to sham group. Compared with model group,CCR2 and CD11b+Ly6 C^+ inflammatory monocytes were also reduced in the administration group( P < 0. 05).Conclusions CCR2 inhibitor RS504393 alleviates renal fibrosis by reducing CD11b^+Ly6C^+ monocyte infiltration.