Overactivation of the renin–angiotensin system (RAS) during obesity disrupts adipocyte metabolic homeostasis and induces endoplasmic reticulum (ER) stress and inflammation; however, underlying mechanisms are not well known. We propose that overexpression of angiotensinogen (Agt), the precursor protein of RAS in adipose tissue or treatment of adipocytes with Angiotensin II (Ang II), RAS bioactive hormone, alters specific microRNAs (miRNA), that target ER stress and inflammation leading to adipocyte dysfunction. Epididymal white adipose tissue (WAT) from B6 wild type (Wt) and transgenic male mice overexpressing Agt (Agt-Tg) in adipose tissue and adipocytes treated with Ang II were used. Small RNA sequencing and microarray in WAT identified differentially expressed miRNAs and genes, out of which miR-690 and mitogen-activated protein kinase kinase 3 (MAP2K3) were validated as significantly up- and down-regulated, respectively, in Agt-Tg, and in Ang II-treated adipocytes compared to respective controls. Additionally, the direct regulatory role of miR-690 on MAP2K3 was confirmed using mimic, inhibitors and dual-luciferase reporter assay. Downstream protein targets of MAP2K3 which include p38, NF-κB, IL-6 and CHOP were all reduced. These results indicate a critical post-transcriptional role for miR-690 in inflammation and ER stress. In conclusion, miR-690 plays a protective function and could be a useful target to reduce obesity.

中文翻译：

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microRNA 690在介导血管紧张素II对炎症和内质网应激的作用中的作用。

肥胖期间肾素-血管紧张素系统（RAS）过度活化会破坏脂肪细胞代谢稳态，并诱导内质网（ER）应激和炎症。但是，底层机制并不为人所知。我们建议，血管紧张素原（Agt），RAS在脂肪组织中的前体蛋白的过度表达或用血管紧张素II（Ang II），RAS生物活性激素治疗脂肪细胞会改变特定的microRNA（miRNA），从而靶向内质网应激和导致脂肪细胞的炎症功能障碍。使用来自B6野生型（Wt）的附睾白色脂肪组织（WAT）和在脂肪组织和Ang II处理的脂肪细胞中过表达Agt（Agt-Tg）的转基因雄性小鼠。WAT中的小RNA测序和微阵列鉴定了差异表达的miRNA和基因，与其中的对照相比，其中经验证的miR-690和丝裂原激活的蛋白激酶激酶3（MAP2K3）在Agt-Tg和Ang II处理的脂肪细胞中分别显着上调和下调。另外，使用模拟物，抑制剂和双重荧光素酶报告基因测定证实了miR-690对MAP2K3的直接调节作用。MAP2K3的下游蛋白靶点（包括p38，NF-κB，IL-6和CHOP）均降低。这些结果表明miR-690在炎症和内质网应激中的关键转录后作用。总之，miR-690起到保护作用，并且可能是减少肥胖的有用靶标。miR-690对MAP2K3的直接调节作用已通过模拟物，抑制剂和双荧光素酶报告基因检测法得以证实。MAP2K3的下游蛋白靶点（包括p38，NF-κB，IL-6和CHOP）均降低。这些结果表明miR-690在炎症和内质网应激中的关键转录后作用。总之，miR-690起到保护作用，并且可能是减少肥胖的有用靶标。miR-690对MAP2K3的直接调节作用已通过模拟物，抑制剂和双荧光素酶报告基因检测法得以证实。MAP2K3的下游蛋白靶点（包括p38，NF-κB，IL-6和CHOP）均降低。这些结果表明miR-690在炎症和内质网应激中的关键转录后作用。总之，miR-690起到保护作用，并且可能是减少肥胖的有用靶标。