Diabetes inhibits corneal epithelial cell migration and tight junction formation in mice and human via increasing ROS and impairing Akt signaling

Jiang, Qiwei; Kaili, Denis; Freeman, Jonaye; Lei, Chong-yang; Geng, Bingchuan; Tan, Tao; He, Jianfeng; Shi, Zhi; Ma, Jianjie; Luo, Yanhong; Chandler, Heather L.; Zhu, Hua

doi:10.1038/s41401-019-0223-y

Cited by 37 publications

(34 citation statements)

References 49 publications

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“…[23][24][25][26][27][28][29] A recent study reported a decrease in TEER in human corneal epithelial cells exposed to 30 mM glucose. 30 Our data are in agreement with this report 30 and additionally demonstrate that corneal epithelial barrier function can also be compromised by moderately high glucose (15 mM). Furthermore, our results also show that high glucose compromises human conjunctival epithelial cell barrier function too.…”

Section: Discussionsupporting

confidence: 92%

“…A literature survey reveals that the effect of high glucose exposure on corneal epithelial cell migration is equivocal with studies reporting a delay, an augmentation, or no change. 30 – 32 Variables such as the use of SV40, telomerase-immortalized, or primary cell types; inclusion/exclusion of serum; and variable epidermal growth factor (EGF) concentrations used in these studies likely contribute to the reported equivocal effect of high glucose exposure on corneal epithelial cell migration. However, our data demonstrate that high glucose exposure does not significantly affect the migration of corneal or conjunctival epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

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Effect of High Glucose on Ocular Surface Epithelial Cell Barrier and Tight Junction Proteins

Alfuraih

Barbarino

Ross

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Patients with diabetes mellitus are reported to have ocular surface defects, impaired ocular surface barrier function, and a higher incidence of corneal and conjunctival infections. Tight junctions are critical for ocular surface barrier function. The present study was designed to investigate the effect of high glucose exposure on human corneal and conjunctival epithelial cell barrier function and tight junction proteins. METHODS. Human corneal and conjunctival epithelial cells were exposed to 15 mM and 30 mM glucose for 24 and 72 hours. The barrier function was measured using transepithelial electrical resistance (TEER). The cell migration was quantified using scratch assay. The cells were harvested for protein extraction and mRNA isolation. Gene and protein expression of claudins, zonula occludens (ZOs), and occludin was quantified using realtime PCR and Western blot. RESULTS. Glucose caused a significant decrease in TEER after 72 hours of exposure in both corneal and conjunctival epithelial cells. Glucose did not cause any notable change in migration of either corneal or conjunctival epithelial cells. Glucose exposure did not cause any notable change in protein expression of claudin-1, ZO-1, ZO-2, ZO-3, or occludin. On the other hand, 15 mM glucose caused an increase in gene expression of claudin-1, claudin-3, ZO-2, ZO-3, and occludin, a likely response to osmotic stress since 15 mM mannitol also caused consistently similar increase in gene expression of these proteins. CONCLUSIONS. High glucose exposure causes impairment of corneal and conjunctival epithelial cell barrier function, but this detrimental effect is not caused by a decrease in expression of tight junction proteins: claudin-1, ZO-1, ZO-2, ZO-3, and occludin.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Effect of High Glucose on Ocular Surface Epithelial Cell Barrier and Tight Junction Proteins

Alfuraih

Barbarino

Ross

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…Chronic hyperglycemia in diabetes is associated with compromised tissue repair and regeneration in diabetes. Human patients with diabetes often develop oculopathy (29)(30)(31)(32)(33)(34), and db/db mice have previously been used for oculopathy research. Following our published protocol of alkaline-induced ocular injury in mice (13), we found that db/db mice subjected to alkaline-induced ocular injury develop compromised reepithelialization, as measured by sustained fluorescein staining (Fig.…”

Section: Compromised Corneal Wound Healing In Db/db Mice Is Amelioratmentioning

confidence: 99%

MG53 Does Not Manifest the Development of Diabetes in db/db Mice

et al. 2020

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MG53 is a member of the TRIM protein family that is predominantly expressed in striated muscles and participates in cell membrane repair. Controversy exists regarding MG53's role in insulin signaling and manifestation of diabetes. We generated db/db mice with either whole-body ablation or sustained elevation of MG53 in the bloodstream in order to evaluate the physiological function of MG53 in diabetes. To quantify the amount of MG53 protein in circulation, we developed a monoclonal antibody against MG53 with high specificity. Western blot using this antibody revealed lower or no change of serum MG53 levels in db/db mice or patients with diabetes compared with control subjects. Neither wholebody ablation of MG53 nor sustained elevation of MG53 in circulation altered insulin signaling and glucose handling in db/db mice. Instead, mice with ablation of MG53 were more susceptible to streptozotocin-induced dysfunctional handling of glucose compared with the wild-type littermates. Alkaline-induced corneal injury demonstrated delayed healing in db/db mice, which was restored by topical administration of recombinant human (rh)MG53. Daily intravenous administration of rhMG53 in rats at concentrations up to 10 mg/kg did not produce adverse effects on glucose handling. These findings challenge the hypothetical function of MG53 as a causative factor for the development of diabetes. Our data suggest that rhMG53 is a potentially safe and effective biologic to treat diabetic oculopathy in rodents.

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“…Additionally, both epithelial and endothelial TJs are disrupted in salivary glands of patients with Sjögren's syndrome (SS) as well as model mice, contributing to salivary hyposecretion (Zhang et al , 2016; Cong et al , 2018). Moreover, TJs are reportedly damaged in other diabetes complications (Jiang et al , 2019; Bu et al , 2020). Cldn1 is upregulated in streptozotocin‐induced mice podocytes, which contributes to the pathogenesis of albuminuria (Hasegawa et al , 2013).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Diabetes inhibits corneal epithelial cell migration and tight junction formation in mice and human via increasing ROS and impairing Akt signaling

Cited by 37 publications

References 49 publications

Effect of High Glucose on Ocular Surface Epithelial Cell Barrier and Tight Junction Proteins

Effect of High Glucose on Ocular Surface Epithelial Cell Barrier and Tight Junction Proteins

MG53 Does Not Manifest the Development of Diabetes in db/db Mice

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

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