Division of Chronic Kidney Disease Pathophysiology, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Nat Rev Nephrol. 2014 Jul;10(7):369-78. doi: 10.1038/nrneph.2014.67. Epub 2014 Apr 22.
Cells use an exquisite network of mechanisms to maintain the integrity and functionality of their protein components. In the endoplasmic reticulum (ER), these networks of protein homeostasis--referred to as proteostasis--regulate protein synthesis, folding and degradation via the unfolded protein response (UPR) pathway. The UPR pathway has two components: the adaptive UPR pathway, which predominantly maintains the ER function or ER proteostasis, and the apoptotic UPR pathway, which eliminates dysfunctional cells that have been subject to long-term or severe ER stress. Dysregulation of the UPR pathway often occurs in glomerular or tubulointerstitial cells under a pathogenic microenvironment, such as oxidative stress, glycative stress or hypoxia. A defective UPR is highly deleterious to renal cell function and viability and is thereby implicated in the pathophysiology of various kidney diseases. Accumulating evidence provides a link between the UPR pathway and mitochondrial structure and function, indicating the important role of ER proteostasis in the maintenance of mitochondrial homeostasis. Restoration of normal proteostasis, therefore, holds promise in protecting the kidney from pathogenic stresses as well as ageing. This Review is focused on the role of the ER stress and UPR pathway in the maintenance of ER proteostasis, and highlights the involvement of the derangement of ER proteostasis and ER stress in various pathogenic stress signals in the kidney.
细胞利用精细的机制网络来维持其蛋白质成分的完整性和功能。在内质网（ER）中，这些蛋白质稳态网络——称为蛋白质稳态——通过未折叠蛋白反应（UPR）途径调节蛋白质的合成、折叠和降解。UPR 途径有两个组成部分：适应性 UPR 途径，主要维持 ER 功能或 ER 蛋白质稳态；凋亡 UPR 途径，消除长期或严重 ER 应激下功能失调的细胞。在致病微环境下，如氧化应激、糖基化应激或缺氧，肾小球或肾小管间质细胞中的 UPR 途径失调经常发生。UPR 途径的失调对肾细胞功能和活力有很大的危害性，因此与各种肾脏疾病的病理生理学有关。越来越多的证据表明 UPR 途径与线粒体结构和功能之间存在联系，表明 ER 蛋白质稳态在维持线粒体稳态中的重要作用。因此，恢复正常的蛋白质稳态有望保护肾脏免受致病应激和衰老的影响。本综述重点介绍了 ER 应激和 UPR 途径在维持 ER 蛋白质稳态中的作用，并强调了 ER 蛋白质稳态和 ER 应激失调在肾脏各种致病应激信号中的参与。
