Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, 05508-000 São Paulo, SP, Brazil.
Federal University of São Paulo, São Paulo, 04023-062, São Paulo, Brazil.
Curr Vasc Pharmacol. 2021;19(2):201-209. doi: 10.2174/1570161118666200606222123.
The endoplasmic reticulum (ER) stress response and the unfolded protein response (UPR) are essential cellular mechanisms to ensure the proper functioning of ER in adverse conditions. However, activation of these pathways has also been associated with insulin resistance and cell death in pathological conditions such as diabetes mellitus. In the present study, we investigated whether stromal cell-derived factor 2 (SDF2)-an ER stress-responsive factor-is related to ER response in placental cells exposed to maternal gestational diabetes mellitus (GDM) or to a hyperglycaemic in vitro condition.
The study aimed to investigate the role of SDF2 in BeWo cells , a trophoblast cell line originating from choriocarcinoma , and in placental tissue under hyperglycaemic conditions.
Protein levels of SDF2 and UPR factors, glucose-related protein 78 (GRP78) and eukaryotic initiation factor 2 alpha (elF2 alpha) were evaluated in the placentae of pregnant women diagnosed with GDM and treated by diet-control (insulin was added when necessary). The mRNA expression of SDF2 and UPR factors CHOP and sXBP1 were assessed in cultured BeWo cells challenged with glucose and treated with or without insulin.
SDF2 expression was increased in the placentae of GDM women treated with diet. However, its values were similar to those of normoglycemic controls when the GDM women were treated with insulin and diet. BeWo cells cultured with high glucose and insulin showed decreased SDF2 expression, while high glucose increased CHOP and sXBP1 expression, which was then significantly reverted with insulin treatment.
Our findings extend the understanding of ER stress and SDF2 expression in placentae exposed to hyperglycaemia, highlighting the relevance of insulin in reducing the levels of ER stress factors in placental cells. Understanding the effect of ER stress partners such as SDF2 on signalling pathways involved in gestation, complicated by hyperglycaemia, is pivotal for basic biomedical research and may lead to new therapeutic possibilities.
内质网（ER）应激反应和未折叠蛋白反应（UPR）是确保 ER 在不利条件下正常发挥功能的重要细胞机制。然而，这些途径的激活也与糖尿病等病理条件下的胰岛素抵抗和细胞死亡有关。在本研究中，我们研究了基质细胞衍生因子 2（SDF2）——一种 ER 应激反应因子——是否与暴露于母体妊娠期糖尿病（GDM）或高血糖体外条件下的胎盘细胞的 ER 反应有关。
该研究旨在探讨 SDF2 在滋养层细胞系 BeWo 细胞和高血糖条件下胎盘组织中的作用。
评估诊断为 GDM 并接受饮食控制（必要时添加胰岛素）治疗的孕妇胎盘和培养的 BeWo 细胞中 SDF2 和 UPR 因子葡萄糖相关蛋白 78（GRP78）和真核起始因子 2α（elF2α）的蛋白水平。用葡萄糖和胰岛素处理 BeWo 细胞，评估 SDF2 和 UPR 因子 CHOP 和 sXBP1 的 mRNA 表达。
饮食治疗的 GDM 妇女胎盘 SDF2 表达增加，但当 GDM 妇女接受胰岛素和饮食治疗时，其值与正常血糖对照组相似。高葡萄糖和胰岛素培养的 BeWo 细胞显示 SDF2 表达降低，而高葡萄糖增加 CHOP 和 sXBP1 表达，随后用胰岛素处理显著逆转。
我们的发现扩展了对暴露于高血糖的胎盘 ER 应激和 SDF2 表达的理解，强调了胰岛素在降低胎盘细胞 ER 应激因子水平方面的重要性。了解 ER 应激伴侣（如 SDF2）对涉及高血糖的妊娠信号通路的影响，对于基础生物医学研究至关重要，并且可能为新的治疗可能性提供线索。
