High Glucose Reduces the Paracellular Permeability of the Submandibular Gland Epithelium via the MiR-22-3p/Sp1/Claudin Pathway
Yan Huang,
Hui-Min Liu,
Qian-Ying Mao,
Xin Cong,
Yan Zhang,
Sang-Woo Lee,
Kyungpyo Park,
Li-Ling Wu,
Ruo-Lan Xiang,
Guang-Yan Yu
Affiliations
Yan Huang
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
Hui-Min Liu
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
Qian-Ying Mao
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
Xin Cong
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
Yan Zhang
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
Sang-Woo Lee
Department of Physiology, School of Dentistry, Seoul National University, Seoul 110-749, Korea
Kyungpyo Park
Department of Physiology, School of Dentistry, Seoul National University, Seoul 110-749, Korea
Li-Ling Wu
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
Ruo-Lan Xiang
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
Guang-Yan Yu
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
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.
