National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China.
Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing 100191, China.
Cells. 2021 Nov 19;10(11):3230. doi: 10.3390/cells10113230.
Tight junctions (TJs) play an important role in water, ion, and solute transport through the paracellular pathway of epithelial cells; however, their role in diabetes-induced salivary gland dysfunction remains unknown. Here, we found that the TJ proteins claudin-1 and claudin-3 were significantly increased in the submandibular glands (SMGs) of db/db mice and high glucose (HG)-treated human SMGs. HG decreased paracellular permeability and increased claudin-1 and claudin-3 expression in SMG-C6 cells. Knockdown of claudin-1 or claudin-3 reversed the HG-induced decrease in paracellular permeability. MiR-22-3p was significantly downregulated in diabetic SMGs and HG-treated SMG-C6 cells. A miR-22-3p mimic suppressed claudin-1 and claudin-3 expression and abolished the HG-induced increases in claudin-1 and claudin-3 levels in SMG-C6 cells, whereas a miR-22-3p inhibitor produced the opposite effects. Specificity protein-1 (Sp1) was enhanced in diabetic SMGs and HG-treated SMG-C6 cells, which promoted claudin-1 and claudin-3 transcription through binding to the corresponding promoters. A luciferase reporter assay confirmed that miR-22-3p repressed Sp1 by directly targeting the Sp1 mRNA 3'-untranslated region (3'-UTR). Consistently, the miR-22-3p mimic suppressed, whereas the miR-22-3p inhibitor enhanced, the effects of HG on Sp1 expression. Taken together, our results demonstrate a new regulatory pathway through which HG decreases the paracellular permeability of SMG cells by inhibiting miR-22-3p/Sp1-mediated claudin-1 and claudin-3 expression.
紧密连接 (TJs) 在通过上皮细胞的细胞旁途径运输水、离子和溶质方面发挥着重要作用；然而，它们在糖尿病引起的唾液腺功能障碍中的作用尚不清楚。在这里，我们发现紧密连接蛋白 claudin-1 和 claudin-3 在 db/db 小鼠和高葡萄糖 (HG) 处理的人颌下腺 (SMG) 中显着增加。HG 降低了 SMG-C6 细胞的细胞旁通透性并增加了 claudin-1 和 claudin-3 的表达。claudin-1 或 claudin-3 的敲低逆转了 HG 诱导的细胞旁通透性降低。miR-22-3p 在糖尿病 SMG 和 HG 处理的 SMG-C6 细胞中显着下调。miR-22-3p 模拟物抑制了 claudin-1 和 claudin-3 的表达，并消除了 HG 诱导的 SMG-C6 细胞中 claudin-1 和 claudin-3 水平的增加，而 miR-22-3p 抑制剂则产生相反的效果。特异性蛋白-1 (Sp1) 在糖尿病 SMG 和 HG 处理的 SMG-C6 细胞中增强，通过结合相应的启动子促进 claudin-1 和 claudin-3 的转录。荧光素酶报告基因测定证实，miR-22-3p 通过直接靶向 Sp1 mRNA 3'-非翻译区 (3'-UTR) 抑制 Sp1。一致地，miR-22-3p 模拟物抑制，而 miR-22-3p 抑制剂增强，HG 对 Sp1 表达的影响。总之，我们的研究结果表明，通过抑制 miR-22-3p/Sp1 介导的 claudin-1 和 claudin-3 表达，HG 通过新的调节途径降低 SMG 细胞的细胞旁通透性。
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