The Proteasome Inhibitor Bortezomib Prevents Lupus Nephritis in the NZB/W F1 Mouse Model by Preservation of Glomerular and Tubulointerstitial Architecture
The Proteasome Inhibitor Bortezomib Prevents Lupus Nephritis in the NZB/W F1 Mouse Model by Preservation of Glomerular and Tubulointerstitial Architecture
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DOI：
10.1159/000334955
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发表时间：
2012-01-01
影响因子：
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通讯作者：
Amann, Kerstin
中科院分区：
文献类型：
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作者：
Hainz, Nadine;Thomas, Susanne;Amann, Kerstin
背景/目的：狼疮性肾炎发病的关键步骤是自身抗体的沉积和随后的补体激活。尽管积极治疗，患者仍可能发展为终末期肾衰竭。因此，需要新的治疗策略。在扩展我们以前发表的数据，我们在这里分析了潜在的肾保护机制硼替佐米（BZ）在实验性狼疮肾炎的形态学变化为重点。方法：雌性NZB x NZW F1小鼠发生狼疮样疾病，伴有广泛性肾炎，最终导致致死性肾衰竭。从18或24周龄开始每周两次静脉注射0.75 mg/kg BZ或安慰剂（PBS）治疗。ELISA法测定抗体产生，定量形态学和免疫组化方法测定肾损伤。结果如下：与PBS处理的动物相比，BZ处理完全抑制了两个BZ处理组中的抗体产生，并防止了肾炎的发展。BZ治疗后肾小球和肾小管间质损伤评分、IV型胶原表达、平均肾小球体积以及肾小管间质增殖和凋亡均显著降低。肾小球超微结构，特别是足细胞损伤和损失的预防BZ治疗。结论：BZ能有效地预防NZB/WF1小鼠肾炎的发生。足细胞超微结构的特异性保护可能是BZ肾保护作用的关键，这也可能是人类狼疮肾炎潜在的新治疗选择。版权所有（C）2012 S. Karger AG，巴塞尔
Background/Aims: Crucial steps in the initiation of lupus nephritis are the deposition of (auto-)antibodies and consequent complement activation. In spite of aggressive treatment patients may develop terminal renal failure. Therefore, new treatment strategies are needed. In extension to our previously published data we here analyzed the potential renoprotective mechanisms of bortezomib (BZ) in experimental lupus nephritis by focusing on morphological changes. Methods: Female NZB x NZW F1 mice develop lupus-like disease with extensive nephritis that finally leads to lethal renal failure. Treatment with 0.75 mg/kg BZ i.v. or placebo (PBS) twice per week started at 18 or 24 weeks of age. Antibody production was measured with ELISA and kidney damage was determined by quantitative morphological and immunohistochemical methods. Results: BZ treatment completely inhibited antibody production in both BZ-treated groups and prevented the development of nephritis in comparison to PBS-treated animals. Glomerular and tubulointerstitial damage scores, collagen IV expression, mean glomerular volume as well as tubulointerstitial proliferation and apoptosis were significantly lower after BZ treatment. Glomerular ultrastructure and in particular podocyte damage and loss were prevented by BZ treatment. Conclusions: BZ effectively prevents the development of nephritis in the NZB/W F1 mouse model. Specific protection of podocyte ultrastructure may critically contribute to renoprotection by BZ, which may also represent a potential new treatment option in human lupus nephritis. Copyright (C) 2012 S. Karger AG, Basel