Cunard Robyn
Research Service and Division of Nephrology-Hypertension, Veterans Affairs San Diego Healthcare System, Veterans Medical Research Foundation, San Diego, CA 92161, USA.
Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
J Clin Med. 2015 Apr 20;4(4):715-40. doi: 10.3390/jcm4040715.
Diabetic kidney disease is the leading worldwide cause of end stage kidney disease and a growing public health challenge. The diabetic kidney is exposed to many environmental stressors and each cell type has developed intricate signaling systems designed to restore optimal cellular function. The unfolded protein response (UPR) is a homeostatic pathway that regulates endoplasmic reticulum (ER) membrane structure and secretory function. Studies suggest that the UPR is activated in the diabetic kidney to restore normal ER function and viability. However, when the cell is continuously stressed in an environment that lies outside of its normal physiological range, then the UPR is known as the ER stress response. The UPR reduces protein synthesis, augments the ER folding capacity and downregulates mRNA expression of genes by multiple pathways. Aberrant activation of ER stress can also induce inflammation and cellular apoptosis, and modify signaling of protective processes such as autophagy and mTORC activation. The following review will discuss our current understanding of ER stress in the diabetic kidney and explore novel means of modulating ER stress and its interacting signaling cascades with the overall goal of identifying therapeutic strategies that will improve outcomes in diabetic nephropathy.
糖尿病肾病是全球终末期肾病的主要病因，也是一个日益严峻的公共卫生挑战。糖尿病肾脏会受到多种环境应激因素的影响，每种细胞类型都已形成了复杂的信号系统，旨在恢复最佳细胞功能。未折叠蛋白反应（UPR）是一种调节内质网（ER）膜结构和分泌功能的稳态途径。研究表明，糖尿病肾脏中的UPR被激活以恢复正常的内质网功能和细胞活力。然而，当细胞在超出其正常生理范围的环境中持续受到应激时，UPR就被称为内质网应激反应。UPR会减少蛋白质合成，增强内质网折叠能力，并通过多种途径下调基因的mRNA表达。内质网应激的异常激活还可诱导炎症和细胞凋亡，并改变自噬和mTORC激活等保护过程的信号传导。以下综述将讨论我们目前对糖尿病肾脏内质网应激的理解，并探索调节内质网应激及其相互作用信号级联反应的新方法，总体目标是确定能够改善糖尿病肾病预后的治疗策略。
