免疫蛋白酶体抑制剂PR957对DOCA-高盐高血压小鼠肾脏纤维化的保护作用

Improvement of proteasome inhibitor PR957 on renal fibrosis in DOCA-salt mice

目的探讨免疫蛋白酶体抑制剂PR957对醋酸脱氧皮质酮(DOCA)盐敏感型高血压小鼠血压和肾脏损伤的保护作用。方法给雄性C57BL/6J小鼠摘除左侧肾脏,2 d后皮下包埋DOCA药片,饮用含0.9%NaCl和0.2%KCl的高盐水,持续3周,复制DOCA-高盐高血压小鼠模型;治疗组小鼠分别给予皮下注射免疫蛋白酶体抑制剂PR957(12 mg/kg/d),每两天1次,持续3周;其余两组皮下注射DMSO与生理盐水的混合液。3周后处死小鼠测定肾脏指数。HE和Masson染色观察肾组织的形态结构变化;qPCR方法检测炎症因子和纤维化因子的表达变化。结果与对照组相比,模型组小鼠血压和肾重/体重显著增高,肾脏病理学检查显示出现肾纤维化改变,collagenⅠ、collagenⅢ、ⅠL-1β、ⅠL-6、TNF-α和MCP1显著增高,差异有统计学意义(P<0.05);PR957治疗后,肾脏指数均明显低于模型组,肾脏病理学检查显示肾纤维化病变明显得到改善,以及炎症因子和纤维化因子的表达水平较模型组显著降低,差异有统计学意义(P<0.05)。结论免疫蛋白酶体抑制剂PR957对DOCA-高盐高血压小鼠的肾脏损伤可以起保护作用。

Objective To investigate the role of proteasome inhibitor in deoxycorticosterone acetate(DOCA)salt-induced hypertensive renal fibrosis in mice.Methods DOCA-salt hypertensive renal fibrosis was induced in wild-type mice by implanting DOCA pills,subcutaneously drinking 0.9%NaCl and 0.2%KCl solution for 4 weeks.Immunoproteasome inhibitor PR-957(12 mg/kg,4 times per week)or vehicle was administrated by?subcutaneously from 1 day before the operation.After treated with PR957 for 3 weeks,the mice were sacrificed to detect the pathological changes of the kidney tissues were observed by HE staining and Masson staining.The expression of collagenⅠand collagenⅢwere detected by qPCR.Results Compared with sham group,the kidney weight/body weight was remarkably increased in DOCA-salt group(P<0.05).The pathological observation of the kidney tissues showed fibrosis changes in DOCA-salt group.The level of collagenⅠ,collagenⅢ,IL-1β,IL-6,TNF-αand MCP1 in the kidney tissues were increased(P<0.05).After treatment with PR957 for 3 weeks,the renal fibrosis lesions were obviously alleviated.Compared with DOCA-salt group,the levels of collagenⅠ,collagenⅢand in the kidney tissues were reduced in DOCA-salt+PR957 group(P<0.05).Conclusion PR957 may prevent the development of renal inflammation and fibrosis in response to DOCA-salt challenge.