Cyclosporine A‐induced gingival overgrowth in renal transplant patients accompanied by epithelial‐to‐mesenchymal transition

Abstract

Objective: To investigate the association between the prevalence of cyclosporin Ainduced gingival overgrowth and the expression of the epithelial-to-mesenchymal transition factors in the gingival tissues of renal transplant patients.Background: Gingival overgrowth (GO) is a frequent complication in organ transplant patients treated with the immunosuppressant cyclosporin A (CsA). The epithelial-tomesenchymal transition (EMT) is considered a factor contributing to CsA-induced GO.However, current knowledge on this topic is sparse.Methods: Sixty-three renal transplant patients were divided into two groups according to the occurrence of GO: those with gingival overgrowth (GO+ group) and those without gingival overgrowth (GO− group). Data on age, sex, and use of immunosuppressant and calcium channel blocker medications, serum creatinine values, peak concentrations of blood CsA, and gingival hyperplasia scores were recorded to identify clinically pathogenic factors. Gingival tissues from five patients with CsA-induced GO and five healthy subjects were selected for histomorphological observation with hematoxylin-eosin staining, Masson staining, and immunohistochemical staining. The mRNA expression of EMT factors was detected with reverse transcriptionquantitative PCR. Results:The use of CsA significantly increased the prevalence of GO in renal transplant patients. The expression of α-SMA, SMAD4, and TGM2 was upregulated and that of E-cadherin was downregulated in the gingival tissues of patients with CsAinduced GO compared with those of the corresponding controls. Conclusion:Treatment with CsA is closely related to the occurrence of GO in renal transplant patients and EMT plays an important role in CsA-induced gingival tissue hyperplasia.

Epithelial-to-mesenchymal transition, inflammation, subsequent collagen production, and reduced proteinase expression cooperatively contribute to cyclosporin-A-induced gingival overgrowth development

“…Next, we detected EMT-related molecules to confirm the EMT characterization in the gingiva of ligatured and un-ligatured WT and Spock1 -Tg mice in the presence or absence of CsA administration and/or experimental periodontitis. CsA-treated WT mice showed downregulation of E-cadherin and no change in Vimentin in the gingiva ( Figures 4A–C ), which is consistent with previous finding in humans ( Chen et al, 2023 ). Induction of periodontitis tend to decrease E-cadherin and increase Vimentin in both WT and CsA-treated WT mice.…”

“…Under CsA treatment, ligatured WT mice exhibited an increase in the fibrotic area in the gingival connective tissue, whereas ligatured Spock1-Tg mice showed a much larger fibrotic area in the gingival connective tissue and thickening of the gingival epithelium (Figures 3F, G). Elongation of the pete pegs with widening was observed in CsA-treated mice with experimental periodontitis, which is consistent with human gingival tissue with CsA-mediated DIGO (Bullon et al, 2007;Chen et al, 2023).…”

“…Characterization of EMT in the gingiva of ligatured and un-ligatured WT and Spock1-Tg mice with or without CsA-administration Next, we detected EMT-related molecules to confirm the EMT characterization in the gingiva of ligatured and un-ligatured WT and 4A-C), which is consistent with previous finding in humans (Chen et al, 2023). Induction of periodontitis tend to decrease E-cadherin and increase Vimentin in both WT and CsA-treated WT mice.…”

“…Spock1 -Tg has been reported to show downregulation of E-cadherin and upregulation of Vimentin in the gingival epithelium, indicating that EMT-like phenotype ( Alshargabi et al, 2020 ). Patients treated with CsA showed downregulation of E-cadherin but no change in Vimentin ( Chen et al, 2023 ), implying CsA might cause partial EMT. WB data consistently showed CsA administration induced decreased E-cadherin and no change in Vimentin in mice ( Figures 4A–C ).…”