| 摘要: |
| 目的了解贝伐珠单抗及不同剂量鼠源贝伐珠单抗对小鼠肾脏的损害作用并探讨其机制。方法将42只C57BL/6小鼠随机分为对照组（12只）及贝伐珠单抗组、低剂量鼠源贝伐珠单抗组、高剂量鼠源贝伐珠单抗组（各10只）。4周后处死小鼠，收集尿液、血清，检测尿微量白蛋白（MA）、血清半胱氨酸蛋白酶抑制剂C（Cys-C）、血尿素氮（BUN）及血肌酐（Cr）；取肾脏组织，HE染色后光镜观察肾脏组织结构，免疫荧光染色观察免疫复合物IgM、IgG、IgA沉积，免疫组化染色观察IgM、IgG、IgA、血管内皮生长因子（VEGF）及Nephrin表达，电镜观察肾脏组织超微结构。结果贝伐珠单抗组、低剂量鼠源贝伐珠单抗组及高剂量鼠源贝伐珠单抗组尿MA、血清Cys-c水平均明显高于对照组，差异均有统计学意义（均P＜0.05）。贝伐珠单抗组和高剂量鼠源贝伐珠单抗组血清BUN、Cr水平均高于对照组，差异均有统计学意义（均P＜0.05）。高剂量鼠源贝伐珠单抗组血清BUN及Cr水平与贝伐珠单抗组、低剂量鼠源贝伐珠单抗组比较，差异均有统计学意义（均P＜0.05）。贝伐珠单抗组免疫荧光IgG+~++；高剂量鼠源贝伐珠单抗组免疫荧光IgM++，免疫组化VEGF表达下调，电镜见肾小球足细胞足突融合。结论贝伐珠单抗引起肾脏损害的机制可能是下调VEGF的表达，引起免疫复合物沉积，导致肾小球内皮细胞足突融合，损害肾小球滤过膜，最终导致蛋白尿的形成及肾功能的损害。 |
| 关键词: 贝伐珠单抗 肾脏损害 蛋白尿 肾脏病理 |
| DOI： |
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| 基金项目:杭州市卫生科技计划；吴阶平医学基金会临床科研专项资助基金 |
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| Bevacizumab-induced renal impairment in mice and its mechanism |
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HE Yi, XU Qunhong, CHEN Xueqin, WANG Ming, FEI Xiao, ZHAO Ning, WANG Benyong, XIE Xiangcheng, QIU Donghao
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Hangzhou Geriatric Hospital
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| Abstract: |
| Objective To investigate bevacizumab-induced renal impairment in mice and its mechanism. Methods Forty two C57BL/6 mice were randomly divided into 4 groups: control group(n=12), bevacizumab group(n=10), low-dose murine bevacizumab group (n=10), high-dose murine bevacizumab group (n=10). The animals were sacrificed 4 weeks after treatment, and urine, serum and renal tissue samples were collected. The urinary micro-albumin (MA), serum cystatin C (Cys-C), blood urea nitrogen(BUN) and creatinine(Cr) were measured. Renal morphological changes and ultrastructural changes were observed by HE staining- light microscopy and electron microscope, respectively. Immune complexes IgG/IgA/IgM deposition in renal
tissue was detected with immunofluorescence and immunohistochemisty, the expression of VEGF and nephrin in renal tissue was examined by immunohistochemisty. Results Compared with control group，the levels of urinary MA and serum cys-C were significantly increased in bevacizumab group, low-dose and high-dose murine bevacizumab groups (P＜0.05). Compared with control group，the levels of serum BUN and Cr were significantly increased in bevacizumab group and high-dose murine bevacizumab group (P＜0.05). The serum levels of BUN and Cr in high-dose murine bevacizumab group were remarkably higher than that in bevacizumab group and low-dose murine bevacizumab group(P＜0.05). Pathological results showed that the immune
complexes IgG deposition in bevacizumab group showed + ~ ++ in immunofluorescence staining. High-dose murine bevacizumab group immunofluorescence IgM deposition ++ and the expression of VEGF was decreased in immunohistochemistry. Meanwhile electron microscopy showed that foot processes of glomerular podocytes were significantly fused in high-dose murine bevacizumab group. Conclusion Bevacizamab-induced renal impairment is associated with down-regulation of VEGF expression and immune complexes deposition, which may lead to the podocytes foot processes fusion and renal function impairment. |
| Key words: Bevacizumab Renal impairment Proteinuria Renal pathology |
