Disruption of tight junctions contributes to hyposalivation of salivary glands in a mouse model of type 2 diabetes

Abstract

Tight junction (TJ) plays an important role in regulating paracellular fluid transport in salivary glands; however, little is known about the involvement of TJs in diabetes salivary glands. This study aimed to investigate the alterations of TJs and their possible contribution in diabetes‐induced hyposalivation. Here, we observed that the morphologies of submandibular glands (SMGs) were impaired, characterized by enlarged acini accumulation with giant secretory granules, which were significantly reduced in atrophic ducts in SMGs of db/db mice, a spontaneous model of type‐2 diabetes. However, the secretory granules were increased and scattered in the acini of diabetes parotid glands (PGs). Other ultrastructural damages including swollen mitochondria, expansive endoplasmic reticulum, and autophagosomes were observed in the diabetes group. The levels of TJ proteins including claudin‐1 (Cldn1) and claudin‐3 (Cldn3) were increased, whereas those of claudin‐4 (Cldn4), occludin (Ocln), and zonula occludens‐1 (ZO‐1) were decreased in SMGs of db/db mice. Higher Cldn1 and Cldn3 and lower claudin‐10 (Cldn10) and Ocln levels were observed in PGs of diabetes mice. Taken together, the structures of SMGs and PGs were impaired in diabetes mice, and the disruption of TJ integrity in both SMGs and PGs may contribute to diabetes‐induced hyposalivation.

Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy

“…In keeping with our earlier statement, that barrier leak in diabetes is systemic and across many tissue types, diabetes-associated hyposalivation was shown to associate with altered TJ protein expression in parotid glands [ 23 ]. In addition, gestational diabetes in a rat model induced increased leak across the placental barrier along with decreased ZO-1 and occludin expression [ 238 ].…”

“…Animal studies have shown that the association holds for much more than simply the intestinal barrier. Huang and Gu [ 23 , 24 ] offer examples of blood–brain barrier (BBB) compromise. Gonzales [ 25 ] address the pulmonary barrier, both endothelial as well as epithelial.…”

Polydatin Alleviates Diabetes-Induced Hyposalivation through Anti-Glycation Activity in db/db Mouse

“…Mucin, the main component of saliva, can change in the pathological condition of the salivary gland. In addition, the over-expression of mucin is promoted by pro-inflammatory cytokines, and cytokine production is associated with an increase in ROS [58][59][60]. Huang et al reported that db/db mice demonstrated that PAS-positive mucins accumulated in the acini of submandibular glands [58].…”

“…In addition, the over-expression of mucin is promoted by pro-inflammatory cytokines, and cytokine production is associated with an increase in ROS [58][59][60]. Huang et al reported that db/db mice demonstrated that PAS-positive mucins accumulated in the acini of submandibular glands [58]. Mucin accumulation in salivary glands also suggests that the salivary secretory function was decreased under hyperglycemic conditions.…”

Pilocarpine improves submandibular gland dysfunction in irradiated rats by downregulating the tight junction protein claudin‐4

“…TJs are intercellular junctional complexes composed of more than 40 different proteins that regulate the transport of water, ions, and solutes through the paracellular pathway in epithelia and endothelia (Baker, 2016). Recently, several members of the claudin multigene family of TJ proteins have been described and some of them are shown to confer selective barrier properties on TJs, such as claudin‐1, claudin‐3, claudin‐4, and claudin‐5 (Huang et al., 2020; Min et al., 2020). Notably, claudin‐4 is mainly distributed and expressed in ductal cells in rodent salivary glands, which may affect the barrier properties of their TJs (Peppi & Ghabriel, 2004; Zhang et al., 2018).…”