Molecular biological function of mesangium predominantly expressed gene, megsin

系膜主要表达基因megsin的分子生物学功能

• 批准号: 15590861
• 负责人: INAGI Reiko
• 金额: $ 2.24万
• 依托单位: Tokai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590861/
• 关键词: serine protease inhibitor; renal failure; serpinopathy; proteinuria; podocytes; endoplasmic reticulum stress; glomerular injuru; transgenic animal; メサンギウム細胞; メグシン; セルピン; トランスジェニックラット

The intracellular polymerization of abnormal serine protease inhibitors (serpins) results in liver or neuronal cell abnormalities recently identified as "serpinopathies". We demonstrate in transgenic rats overexpressing megsin, a recently discovered serpin located in the kidney, produce renal and pancreatic lesions characteristic of serpinopathies. Megsin expression is elevated in a variety of organs including kidney and pancreas. Periodic acid Schiff-positive intracellular inclusions develop only in the two latter organs. They correspond to electron dense deposits, shown to contain megsin by immunohistochemistry and immunoelectron microscopy. In the kidney, inclusions are located mainly in the endoplasmic reticulum (ER) of glomerular epithelial, distal tubules and collecting ducts and are associated with massive proteinuria and an impaired renal function. In the pancreas, similar inclusions are found in the exocrine and Langerhans islet cells, where islet b-cells are reduced due to apoptosis. They are associated with diabetes with low insulin levels. An imbalance between protein load and folding capacity is referred to as ER stress. As a defense mechanism, cells express ER stress inducible chaperons such as oxygen regulated protein 150 (ORP150) and glucose regulated proteins (GRPs). The expression level of ORP150 and GRPs were markedly up-regulated in podocytes of megsin transgenic rats, subsequently developed podocyte injury. Rats overexpressing a mutant megsin, characterized by a deficient conformational transition activity, do not develop the serpinopathy associated with renal dysfunction, proteinuria, hyperglycemia and ER stress, suggesting that some conformational flexibility of the serpin is required for the development of serpinopathy. The present model of serpinopathy is the first to involve the kidney and pancreas, and demonstrates a crucial role for ER stress in podocyte injury.

异常丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）的细胞内聚合导致肝脏或神经元细胞异常，最近被鉴定为“丝氨酸蛋白酶抑制剂病”。我们在转基因大鼠中证明过度表达megsin（一种最近发现的位于肾脏的丝氨酸蛋白酶抑制剂）会产生丝氨酸蛋白酶抑制剂病特征的肾脏和胰腺病变。 Megsin 表达在包括肾脏和胰腺在内的多种器官中升高。高碘酸希夫阳性细胞内包涵体仅在后两个器官中发育。它们对应于电子致密沉积物，通过免疫组织化学和免疫电子显微镜显示含有 megsin。在肾脏中，包涵体主要位于肾小球上皮的内质网（ER）、远端肾小管和集合管中，与大量蛋白尿和肾功能受损有关。在胰腺中，外分泌细胞和朗格汉斯胰岛细胞中也发现了类似的内含物，其中胰岛 b 细胞因凋亡而减少。它们与胰岛素水平低的糖尿病有关。蛋白质负荷和折叠能力之间的不平衡称为内质网应激。作为一种防御机制，细胞表达 ER 应激诱导伴侣，例如氧调节蛋白 150 (ORP150) 和葡萄糖调节蛋白 (GRP)。 megsin转基因大鼠足细胞中ORP150和GRPs的表达水平显着上调，随后发生足细胞损伤。过表达突变型 megsin 的大鼠（其特征是构象转变活性缺陷）不会发生与肾功能障碍、蛋白尿、高血糖和 ER 应激相关的丝氨酸蛋白酶抑制剂病，这表明丝氨酸蛋白酶抑制剂的某些构象灵活性是丝氨酸蛋白酶抑制剂病的发生所必需的。目前的丝氨酸病模型是第一个涉及肾脏和胰腺的模型，并且证明了内质网应激在足细胞损伤中的关键作用。

项目成果

Annual Review腎臓

年度回顾肾脏

• 发表时间: 2008
• 作者: Matsuzawa A.;et. al.;伊藤恭典
• 通讯作者: 伊藤恭典

Manotham K, et al.: "Transdifferentiation of cultured tubular cells induced by hypoxia."Kidney Int. 65. 871-880 (2004)

Manotham K 等人：“缺氧诱导培养的肾小管细胞的转分化。”Kidney Int。

Onogi H, et al.: "Proteomics and mesangial cell : serpin, megsin and plasmin."Contrib Nephrol. 141. 212-220 (2004)

Onogi H 等人：“蛋白质组学和系膜细胞：丝氨酸蛋白酶抑制剂、megsin 和纤溶酶。”Contrib Nephrol。

Hypoxia-induced apoptosis in cultured glomerular endothelial cells: Involvement of mitochondrial pathways

• DOI: 10.1046/j.1523-1755.2003.00301.x
• 发表时间: 2003-12-01
• 期刊: KIDNEY INTERNATIONAL
• 影响因子: 19.6
• 作者: Tanaka, T;Miyata, T;Nangaku, M
• 通讯作者: Nangaku, M

Serpinopathy and endoplasmic reticulum (ER) stress

丝氨酸病和内质网 (ER) 应激

• 期刊: Med Elect Microsc (In press)
• 作者: Tanaka T;Miyata T;Inagi R;Kurokawa K;Adler S;Fujita T;Nangaku M.;Inagi R et al.;Inagi R et al.
• 通讯作者: Inagi R et al.