Abstract
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.
Highlights
IntroductionSaliva is vital to oral and systemic health, as it contributes to mechanical cleaning and plays a protective role in the oral cavity through physiological and biochemical mechanisms [1]
Transmission electron microscopy images of submandibular glands (SMGs) showed that the Tight junctions (TJs) appeared as a narrow and continuous seal in the apical region between neighboring acini in db/m mice, while the lateral membranes of tight junctions appeared to be less well defined but closely aligned compared with db/m mice (Figure 1A,B)
Immunofluorescence staining images showed that claudin-1 and claudin-3 were predominantly expressed in the apicolateral and basolateral membranes of acini in the mouse SMG, and their staining intensities were enhanced in the db/db group
Summary
Saliva is vital to oral and systemic health, as it contributes to mechanical cleaning and plays a protective role in the oral cavity through physiological and biochemical mechanisms [1]. Patients with diabetes exhibit a high prevalence of salivary gland dysfunction, which disturbs the homeostasis of the oral cavity by altering the salivary composition and volume [2,3]. Hyposalivation induced by salivary gland dysfunction negatively affects the quality of life of patients with diabetes by interfering with their eating and speaking functions and nutritional state, enhancing the risks of oral infection, dental caries, and periodontal diseases [4]. Despite intensive research on the alterations in salivary flow and components in patients with diabetes, the molecular mechanism of diabetic hyposalivation remains largely unknown
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