Molecular biological function of mesangium predominantly expressed gene, megsin

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”。我们证明，在转基因大鼠过度表达megsin，最近发现的丝氨酸蛋白酶抑制剂位于肾脏，产生肾脏和胰腺病变的丝氨酸蛋白酶抑制剂病的特点。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只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巨蛋白。在肾脏中，包涵体主要位于肾小球上皮、远端小管和集合管的内质网（ER）中，并与大量蛋白尿和肾功能受损相关。在胰腺中，在外分泌和朗格汉斯胰岛细胞中发现类似的内含物，其中胰岛b细胞由于凋亡而减少。它们与低胰岛素水平的糖尿病有关。蛋白质负荷和折叠能力之间的不平衡被称为ER应激。作为一种防御机制，细胞表达ER应激诱导型分子伴侣，如氧调节蛋白150（ORP 150）和葡萄糖调节蛋白（GRP）。megsin转基因大鼠足细胞中ORP 150和GRP的表达水平显著上调，随后出现足细胞损伤。大鼠过度表达突变型megsin，其特征在于缺乏构象转换活性，不发展与肾功能障碍，蛋白尿，高血糖症和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一些构象灵活性是发展丝氨酸蛋白酶抑制剂病所必需的。目前的丝氨酸蛋白酶抑制剂病模型是第一个涉及肾脏和胰腺的模型，并证明了ER应激在足细胞损伤中的关键作用。

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.