Involvement of endoplasmic reticulum (ER) stress in podocyte injury induced by excessive protein accumulation
Involvement of endoplasmic reticulum (ER) stress in podocyte injury induced by excessive protein accumulation
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DOI：
10.1111/j.1523-1755.2005.00736.x
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发表时间：
2005-12-01
影响因子：
19.6
通讯作者：
Miyata, T
中科院分区：
文献类型：
--
作者：
Inagi, R;Nangaku, M;Miyata, T
背景蛋白质负载和折叠能力之间的不平衡被称为内质网（ER）应激。作为一种防御机制，细胞表达ER应激诱导型伴侣蛋白，如氧调节蛋白150（ORP 150）和葡萄糖调节蛋白（GRP）。虽然ER应激在各种疾病中很重要，但ER应激在肾脏疾病中的病理生理作用仍然难以捉摸。在这里，我们研究了ER应激蛋白在培养的大鼠足细胞中的表达，以及我们最近开发的足细胞ER内异常蛋白质滞留的动物模型（即，megsin转基因大鼠）。通过Western blotting、免疫组化和共聚焦显微镜观察经衣霉素、A23187、SNAP、缺氧和高血糖处理的足细胞以及megsin转基因大鼠的肾组织和肾小球中ER应激诱导蛋白（ORP 150、GRP78和GRP94）的表达。培养的足细胞表明，处理与衣霉素，A23187，和SNAP，但不是缺氧或高血糖，上调ER应激蛋白的表达。从megsin转基因大鼠分离的肾小球提取物揭示了足细胞中ER应激分子伴侣的显著上调，这得到了免疫组织化学分析的支持。共聚焦显微镜显示足细胞中的ER应激与细胞损伤有关。过表达突变型megsin的转基因大鼠足细胞，没有ER内聚合的能力，不表现出ER应激或足细胞损伤，提示聚合型megsin的ER滞留的致病作用。这篇文章暗示了足细胞内质网中过量蛋白质的积累在诱导内质网应激和相关足细胞损伤中的关键作用。
Background. An imbalance between protein load and folding capacity is referred to as endoplasmic reticulum ( ER) stress. As a defense mechanism, cells express ER stress inducible chaperons, such as oxygen-regulated proteins 150 (ORP150) and glucose-regulated proteins (GRPs). While ER stress is important in various diseases, a pathophysiologic role for ER stress in kidney disease remains elusive. Here we investigate expression of ER stress proteins in cultured rat podocytes as well as in our recently developed animal model of abnormal protein retention within the ER of podocytes (i.e., megsin transgenic rat).Methods. The expression of ER stress inducible proteins (ORP150, GRP78, or GRP94) in cultured podocytes treated with tunicamycin, A23187, SNAP, hypoxia, or hyperglycemia, and the renal tissues or isolated glomeruli from megsin transgenic rats was analyzed by Western blotting analysis, immunohistochemistry, or confocal microscopy.Results. Cultured podocytes demonstrated that treatment with tunicamycin, A23187, and SNAP, but not hypoxia or hyperglycemia, up-regulate expression of ER stress proteins. Extracts of isolated glomeruli from megsin transgenic rats reveal marked up-regulation of ER stress chaperones in podocytes, which was supported by immunohistochemical analysis. Confocal microscopy revealed that ER stress in podocytes was associated with cellular injury. Podocytes of transgenic rats overexpressing a mutant megsin, without the capacity for polymerization within the ER, do not exhibit ER stress or podocyte damage, suggesting a pathogenic role of ER retention of polymerized megsin.Conclusion. This paper implicates a crucial role for the accumulation of excessive proteins in the podocyte ER in the induction of ER stress and associated podocyte injury.