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Crosstalk between endoplasmic reticulum stress and oxidative stress in the progression of diabetic nephropathy
Cell Stress and Chaperones ( IF 3.8 ) Pub Date : 2020-11-07 , DOI: 10.1007/s12192-020-01176-z
Paul Victor 1 , Dhamodharan Umapathy 2 , Leema George 3 , Udyama Juttada 3 , Goutham V Ganesh 1 , Karan Naresh Amin 1 , Vijay Viswanathan 3 , Kunka Mohanram Ramkumar 1, 2
Affiliation  

Increasing evidence in substantiating the roles of endoplasmic reticulum stress, oxidative stress, and inflammatory responses and their interplay is evident in various diseases. However, an in-depth mechanistic understanding of the crosstalk between the intracellular stress signaling pathways and inflammatory responses and their participation in disease progression has not yet been explored. Progress has been made in our understanding of the cross talk and integrated stress signaling network between endoplasmic reticulum stress and oxidative stress towards the pathogenesis of diabetic nephropathy. In this present study, we studied the crosstalk between the endoplasmic reticulum stress and oxidative stress by understanding the role of protein disulfide isomerase and endoplasmic reticulum oxidase 1α, a key player in redox protein folding in the endoplasmic reticulum. We had recruited a total of 90 subjects and divided into three groups (control (n = 30), type 2 diabetes mellitus (n = 30), and diabetic nephropathy (n = 30)). We found that endoplasmic reticulum stress markers, activating transcription factor 6, inositol-requiring enzyme 1α, protein kinase RNA-like endoplasmic reticulum kinase, C/EBP homologous protein, and glucose-regulated protein-78; oxidative stress markers, thioredoxin-interacting protein and cytochrome b-245 light chain; and the crosstalk markers, protein disulfide isomerase and endoplasmic reticulum oxidase-1α, were progressively elevated in type 2 diabetes mellitus and diabetic nephropathy subjects. The association between the crosstalk markers showed a positive correlation with endoplasmic reticulum stress and oxidative stress markers. Further, the interplay between endoplasmic reticulum stress and oxidative stress was investigated in vitro using a human leukemic monocytic cell line under a hyperglycemic environment and examined the expression of protein disulfide isomerase and endoplasmic reticulum oxidase-1α. DCFH-DA assay and flow cytometry were performed to detect the production of free radicals. Further, phosphorylation of eIF2α in high glucose–exposed cells was studied using western blot. In conclusion, our results shed light on the crosstalk between endoplasmic reticulum stress and oxidative stress and significantly contribute to the onset and progression of diabetic nephropathy and therefore represent the major therapeutic targets for alleviating micro- and macrovascular complications associated with this metabolic disturbance.



中文翻译:

内质网应激与氧化应激在糖尿病肾病进展中的相互作用

越来越多的证据证实内质网应激、氧化应激和炎症反应的作用及其相互作用在各种疾病中都很明显。然而,尚未探索对细胞内应激信号通路和炎症反应之间的串扰及其参与疾病进展的深入机制理解。我们对内质网应激和氧化应激之间的串扰和综合应激信号网络对糖尿病肾病发病机制的理解取得了进展。在本研究中,我们通过了解蛋白质二硫键异构酶和内质网氧化酶 1α 的作用,研究了内质网应激和氧化应激之间的相互作用,在内质网中氧化还原蛋白折叠的关键参与者。我们共招募了 90 名受试者,分为三组(对照组(n  = 30)、2 型糖尿病 ( n  = 30) 和糖尿病肾病 ( n = 30))。我们发现内质网应激标志物、激活转录因子 6、肌醇需要酶 1α、蛋白激酶 RNA 样内质网激酶、C/EBP 同源蛋白和葡萄糖调节蛋白 78;氧化应激标志物、硫氧还蛋白相互作用蛋白和细胞色素 b-245 轻链;串扰标志物,蛋白质二硫键异构酶和内质网氧化酶-1α,在 2 型糖尿病和糖尿病肾病受试者中逐渐升高。串扰标记之间的关联与内​​质网应激和氧化应激标记呈正相关。更远,在高血糖环境下使用人类白血病单核细胞系在体外研究了内质网应激和氧化应激之间的相互作用,并检查了蛋白质二硫键异构酶和内质网氧化酶-1α的表达。进行DCFH-DA测定和流式细胞术以检测自由基的产生。此外,使用蛋白质印迹研究了高葡萄糖暴露细胞中 eIF2α 的磷酸化。总之,我们的结果阐明了内质网应激和氧化应激之间的相互作用,并显着促进了糖尿病肾病的发生和进展,因此代表了减轻与这种代谢紊乱相关的微血管和大血管并发症的主要治疗靶点。

更新日期:2020-11-09
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