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中华肾病研究电子杂志 ›› 2025, Vol. 14 ›› Issue (02) : 104 -109. doi: 10.3877/cma.j.issn.2095-3216.2025.02.007

综述

通过调控内质网应激信号通路治疗糖尿病肾病的研究进展
朱蓉蓉1, 王俭勤2,()   
  1. 1. 730000 甘肃,兰州大学
    2. 730030 甘肃,兰州大学第二医院
  • 收稿日期:2024-11-26 出版日期:2025-04-28
  • 通信作者: 王俭勤
  • 基金资助:
    甘肃省临床医学研究中心(21JR7RA436)

Research progress on treating diabetic kidney disease by regulating endoplasmic reticulum stress signaling pathway

Rongrong Zhu1, Jianqin Wang2,()   

  1. 1. Lanzhou Univesity, Lanzhou 730000
    2. Second Hospital of Lanzhou University, Lanzhou 730030; Gansu Province, China
  • Received:2024-11-26 Published:2025-04-28
  • Corresponding author: Jianqin Wang
引用本文:

朱蓉蓉, 王俭勤. 通过调控内质网应激信号通路治疗糖尿病肾病的研究进展[J/OL]. 中华肾病研究电子杂志, 2025, 14(02): 104-109.

Rongrong Zhu, Jianqin Wang. Research progress on treating diabetic kidney disease by regulating endoplasmic reticulum stress signaling pathway[J/OL]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2025, 14(02): 104-109.

糖尿病肾病作为糖尿病的特征性微血管并发症已成为慢性肾脏病的首要病因,然而仍然缺乏能够阻止其向终末期肾脏病进展的有力手段。近年来的研究提示,内质网应激参与了糖尿病肾病的发生和进展,内质网应激信号通路有可能成为治疗糖尿病肾病的新靶点。本文综述了通过调控内质网应激信号通路治疗糖尿病肾病的研究进展。

Diabetic nephropathy (DKD), as a characteristic microvascular complication of diabetes, has become the leading cause of chronic kidney disease. However, there is still a lack of effective means to prevent its progression to end-stage renal disease (ESRD). Recent studies have suggested that endoplasmic reticulum stress (ERS) was involved in the occurrence and progression of DKD, and the ERS signaling pathway may become a new target for the treatment of DKD. This article reviewed the research progress on treating DKD by regulating the endoplasmic reticulum stress signaling pathway.

表1 内质网应激的影响机制
项目 影响方式 意义
致病分子机制方面
 肾表皮生长因子受体[10] 通过EGFR/ Akt/ 活性氧/ ERS 信号通路 可预防和治疗糖尿病肾病进行性的肾损害
 高糖刺激[11] 激活未折叠蛋白反应途径,增加活性氧的积累,增强内质网应激 改善糖代谢,为临床治疗提供新思路
 血管紧张素Ⅱ受体通路[12] 血管紧张素Ⅱ在内质网应激诱导的细胞凋亡中起负性作用,可减少其诱导的肾细胞凋亡,也可诱导分子伴侣的增加 可通过调控此通路减轻糖尿病肾病的症状,延缓疾病的进展
 自噬[13] 通过内质网相关蛋白降解作用以清除未折叠和错误折叠的蛋白 减少内质网应激,肾小球上皮细胞通透性降低,减轻糖尿病肾病症状,延缓疾病进展
组织病理学结构方面
 足细胞损伤[17] 摄取蛋白质且有很高的内吞活性,摄取的白蛋白可通过活性氧-内质网应激途径使得整合素-β1 下降,抑制整合素-β1 的翻译和糖基化 降低足突对肾小球基底膜的黏附力,导致更多的蛋白尿,蛋白尿导致糖尿病肾病肾小球功能障碍,调控内质网应激可减少蛋白尿,延缓疾病进展
 肾小球系膜细胞损伤[17] 高糖和活性氧可诱导内质网应激的发生,导致系膜细胞增殖和细胞外基质的生成增多,活性氧可激活转录因子,增加细胞外基质基因的表达,使糖尿病肾病逐渐进展为终末期肾病 抑制高糖和活性氧的可减少内质网应激的发生,延缓糖尿病肾病的进展
 肾小球内皮细胞损伤[18] 血管紧张素Ⅱ可以拮抗血管生成素 1 与Tie2 受体结合,显著降低GRP78,GRP94、p-PERK 和CHOP 的表达 减轻内质网应激诱导的细胞损伤和凋亡,可使肾小球内皮细胞功能得到改善,延缓糖尿病肾病的进展
 肾小管上皮细胞[20] 高糖处理的肾小管上皮细胞中,可通过激活转录因子6-PERK 途径抑制肾小管上皮细胞-间质转化 延缓糖尿病肾病的进展
表2 调控内质网应激的药物汇总
药物名称 药物类型 作用方式
化学合成物药
 牛磺熊去氧胆酸[28] 分子伴侣 诱导的葡萄糖调节蛋白78 的表达,有效的转运蛋白质,减少蛋白质的聚集来缓解内质网应激
 4-苯基丁酸[29] 内质网应激抑制剂 疏水结构域与未折叠蛋白质的暴露疏水片段相互作用,从而促进蛋白质折叠并防止蛋白质聚集,缓解内质网应激
 阿利吉仑[33-34] 肾素抑制剂 显著抑制了棕榈酸诱导的肾小管细胞内质网应激水平,同时抑制促纤维化生长因子和促炎性细胞因子的表达,从而改善糖尿病肾病肾损伤
 雷帕霉素[35] 内质网应激调节因子 针对性抑制肌醇需求酶1α 通路,从而减轻内质网应激,促进自噬的激活,避免引起缺血再灌注损伤
 依达拉奉[37] 抗氧化剂 抑制真核翻译起始因子2 亚基α 和C/ EBP 同源蛋白,防止由脂质过氧化和内质网应激引起的细胞缺氧
天然产物与中药活性成分
 槲皮素[38] 抗氧化剂、内质网应激抑制剂 激活沉默信息调节因子2 相关酶1/ AMP 活化蛋白激酶信号通路以抑制内质网应激
 槲皮素3-O-木糖苷 抗氧化剂 抑制细胞中活性氧的产生来抑制内质网应激[39]
 番红花[40] 抗氧化剂 抑制活性氧驱动的内质网应激通道
 黄芪甲苷Ⅳ[41] 抗氧化剂 降低蛋白激酶受体样内质网激酶、激活转录因子4 及C/ EBP 同源蛋白的活性,从而减少由内质网应激引起的足细胞凋亡现象
 大黄素[42] 抗氧化剂 干预蛋白激酶受体样内质网激酶-真核翻译起始因子2 亚基α 信号传递途径,有助于减轻足细胞凋亡
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