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，最近被确定为“丝氨酸病”。我们证明了在转基因大鼠中过度表达megsin，一种最近发现的位于肾脏的蛇形蛋白，产生具有蛇形蛋白病特征的肾脏和胰腺病变。Megsin的表达在包括肾脏和胰腺在内的多种器官中升高。周期性酸性席夫阳性细胞内包涵体只在后两个器官中出现。它们对应于电子致密沉积物，通过免疫组织化学和免疫电镜显示含有巨噬蛋白。在肾脏中，包涵体主要位于肾小球上皮的内质网（ER）、远端小管和集合管，并与大量蛋白尿和肾功能受损有关。在胰腺中，外分泌和朗格汉斯胰岛细胞中也发现了类似的包涵体，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被称为内质网应激。作为一种防御机制，细胞表达内质网应激诱导的伴侣蛋白，如氧调节蛋白150 （ORP150）和葡萄糖调节蛋白（GRPs）。在megsin转基因大鼠足细胞中，ORP150和GRPs的表达水平显著上调，随后发生足细胞损伤。大鼠过度表达突变megsin，其特征是构象转换活性不足，不会发生与肾功能障碍、蛋白尿、高血糖和内质网应激相关的丝状蛋白病，这表明丝状蛋白的一些构象灵活性是丝状蛋白病发生所必需的。目前的蛇形病变模型是第一个涉及肾脏和胰腺的模型，并证明内质网应激在足细胞损伤中起关键作用。

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.