Pathophysiological significances of ER stress in the kidney : A lesson from novel renal failure model rats

蛋白质负荷和折叠能力之间的不平衡被称为内质网（ER）应激。已知内质网应激与一些蛋白质构象疾病的进展有关，如神经元障碍和糖尿病。然而内质网应激在肾脏疾病中的作用尚不清楚。在本研究中，我们评估肾内质网应激的病理生理意义。在过表达megsin（最近发现的一种肾丝氨酸蛋白酶抑制剂（serpin））的转基因大鼠中，观察到异常serpin在细胞内聚合引起的具有丝氨酸病特征的肾脏病变。巨噬蛋白转基因大鼠的肾小球上皮细胞和远端小管细胞内质网中大量巨噬蛋白被聚合并形成细胞内包涵体。这些现象与蛋白尿有关。megsin转基因大鼠足细胞内质网应激水平显著升高，随后发生足细胞损伤。相反，过度表达巨蛋白突变体的大鼠，其特征是构象转换活性不足，没有发生与肾功能障碍、蛋白尿和内质网应激相关的丝状病变。在实验性肾病大鼠中，我们证明了内质网应激在暴露于蛋白尿的小管细胞中被诱导，随后发生凋亡。我们利用培养的大鼠小管细胞进行的体外研究也表明，暴露于高浓度白蛋白诱导内质网应激与这些细胞的凋亡有关。这些结果首次提示内质网应激在肾脏疾病中的病理生理意义。

An imbalance between protein load and folding capacity is referred to as endoplasmic reticulum (ER) stress. ER stress is known to be related to progression of some protein conformational diseases such as neuronal disorder and diabetes mellitus. However a role of ER stress in the kidney diseases is still unclear yet. In this study, we evaluate pathophysiological significances of ER stress in the kidney.In transgenic rats overexpressing megsin, a recently discovered renal serine protease inhibitor (serpin), renal lesions characteristic of serpinopathies, caused by the intracellular polymerization of abnormal serpins, were observed. Large amount of megsin was polymerized and formed intracellular inclusions mainly in the ER of glomerular epithelial and distal tubular cells of megsin transgenic rats. These phenomena were associated with proteinuria. The ER stress level was markedly increased in podocytes of megsin transgenic rats, and subsequently developed podocyte injury. In contrast, rats overexpressing a mutant megsin, characterized by a deficient conformational transition activity, did not develop the serpinopathy associated with renal dysfunction, proteinuria, and ER stress.In experimental nephrosis rats, we demonstrated that ER stress was induced in the tubular cells exposed to proteinuria followed by apoptosis. Our in vitro study utilizing cultured rat tubular cells also showed that exposure to high concentration of albumin induced ER stress associated with apoptosis in these cells.These results suggest for the first time pathophysiological significances of ER stress in renal diseases.