Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid-Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
Departmento de Inmunología, Oftalmología y Otorrinolaringología, Facultad de Psicología, Universidad Complutense Madrid, Spain.
Clin Sci (Lond). 2021 Jan 15;135(1):143-159. doi: 10.1042/CS20201137.
Myocardial infarction (MI) is associated with renal alterations resulting in poor outcomes in patients with MI. Renal fibrosis is a potent predictor of progression in patients and is often accompanied by inflammation and oxidative stress; however, the mechanisms involved in these alterations are not well established. Endoplasmic reticulum (ER) plays a central role in protein processing and folding. An accumulation of unfolded proteins leads to ER dysfunction, termed ER stress. Since the kidney is the organ with highest protein synthesis fractional rate, we herein investigated the effects of MI on ER stress at renal level, as well as the possible role of ER stress on renal alterations after MI. Patients and MI male Wistar rats showed an increase in the kidney injury marker neutrophil gelatinase-associated lipocalin (NGAL) at circulating level or renal level respectively. Four weeks post-MI rats presented renal fibrosis, oxidative stress and inflammation accompanied by ER stress activation characterized by enhanced immunoglobin binding protein (BiP), protein disulfide-isomerase A6 (PDIA6) and activating transcription factor 6-alpha (ATF6α) protein levels. In renal fibroblasts, palmitic acid (PA; 50-200 µM) and angiotensin II (Ang II; 10-8 to 10-6M) promoted extracellular matrix, superoxide anion production and inflammatory markers up-regulation. The presence of the ER stress inhibitor, 4-phenylbutyric acid (4-PBA; 4 µM), was able to prevent all of these modifications in renal cells. Therefore, the data show that ER stress mediates the deleterious effects of PA and Ang II in renal cells and support the potential role of ER stress on renal alterations associated with MI.
心肌梗死（MI）与肾脏改变有关，导致 MI 患者的预后不良。肾纤维化是患者进展的有力预测指标，常伴有炎症和氧化应激；然而，这些改变涉及的机制尚未得到很好的确定。内质网（ER）在蛋白质加工和折叠中起核心作用。未折叠蛋白的积累会导致 ER 功能障碍，称为 ER 应激。由于肾脏是蛋白质合成分数率最高的器官，因此我们在此研究了 MI 对肾脏水平 ER 应激的影响，以及 ER 应激在 MI 后肾脏改变中的可能作用。患者和 MI 雄性 Wistar 大鼠分别在循环水平或肾脏水平上表现出肾脏损伤标志物中性粒细胞明胶酶相关脂质运载蛋白（NGAL）的增加。MI 后 4 周，大鼠出现肾脏纤维化、氧化应激和炎症，同时伴有 ER 应激激活，表现为免疫球蛋白结合蛋白（BiP）、蛋白二硫键异构酶 A6（PDIA6）和激活转录因子 6-α（ATF6α）蛋白水平增强。在肾成纤维细胞中，棕榈酸（PA；50-200 μM）和血管紧张素 II（Ang II；10-8 至 10-6M）促进细胞外基质、超氧阴离子产生和炎症标志物的上调。内质网应激抑制剂 4-苯丁酸（4-PBA；4 μM）的存在能够防止肾细胞的所有这些改变。因此，数据表明 ER 应激介导 PA 和 Ang II 在肾细胞中的有害作用，并支持 ER 应激在与 MI 相关的肾脏改变中的潜在作用。
