贝伐珠单抗对小鼠肾脏损害作用及机制研究

来源 :浙江医学 | 被引量 : 0次 | 上传用户:zel0088
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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。 Objective To investigate the effect of bevacizumab and different doses of mouse bevacizumab on the kidney in mice and its mechanism. Methods Forty-two C57BL / 6 mice were randomly divided into control group (12 mice) and bevacizumab group (low-dose bevacizumab group) and high-dose bevacizumab group 10). After 4 weeks, the mice were sacrificed and urine, serum, urinary albumin (MA), serum Cys-C, BUN and Cr were measured. The kidneys were harvested and the kidneys were stained by HE staining. Immunohistochemical staining of immunocomplexes, IgM, IgG and IgA were observed. The expressions of IgM, IgG, IgA, VEGF and Nephrin were observed by immunohistochemistry. Electron microscopy of renal tissue ultrastructure. Results The urinary MA and serum Cys-c levels were significantly higher in the bevacizumab group, the low-dose mouse-derived bevacizumab group and the high-dose mouse bevacizumab group, with significant differences (All P <0.05). The levels of serum BUN and Cr in bevacizumab group and high-dose bevacizumab group were significantly higher than those in control group (all P <0.05). The serum levels of BUN and Cr in high-dose murine bevacizumab group were significantly lower than those in low-dose bevacizumab group and bevacizumab group (all P <0.05). The immunofluorescence of bevacizumab group IgG + ~ + +; high-dose mouse bevacizumab group immunofluorescence IgM + +, immunohistochemical VEGF expression was down, electron microscopy, glomerular podocyte foot process fusion. Conclusion The mechanism of bevacizumab-induced renal damage may be to down-regulate the expression of VEGF, cause the deposition of immune complexes, lead to the fusion of foot processes of glomerular endothelial cells, damage the glomerular filtration membrane and finally lead to the formation of proteinuria and kidney Functional damage.
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