Lobeglitazone attenuates fibrosis in corneal fibroblasts by interrupting TGF-beta-mediated Smad signaling.
Graefes Arch Clin Exp Ophthalmol
; 260(1): 149-162, 2022 Jan.
Article
en En
| MEDLINE
| ID: mdl-34468828
ABSTRACT
PURPOSE:
Transforming growth factor beta 1 (TGF-ß1) is an important cytokine released after ocular surface injury to promote wound healing. However, its persistence at the injury site triggers a fibrotic response that leads to corneal scarring and opacity. Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor gamma (PPAR-γ) ligands used to regulate glucose and lipid metabolism in the management of type 2 diabetes. Studies have also showed TZDs have antifibrotic effect. In this study, we investigated the antifibrotic effect of the TZD lobeglitazone on TGF-ß1-induced fibrosis in corneal fibroblasts.METHODS:
Human primary corneal fibroblasts were cultivated and treated with TGF-ß1 (5 ng/mL) to induce fibrosis, with or without pre-treatments with different concentrations of lobeglitazone. Myofibroblast differentiation and extracellular matrix (ECM) protein expression was evaluated by western blotting, immunofluorescence, real-time PCR, and collagen gel contraction assay. The effect of lobeglitazone on TGF-ß1-induced reactive oxygen species (ROS) generation was evaluated by DCFDA-cellular ROS detection assay kit. Signaling proteins were evaluated by western blotting to determine the mechanism underlying the antifibrotic effect.RESULTS:
Our results showed lobeglitazone attenuated TGF-ß1-induced ECM synthesis and myofibroblast differentiation of corneal fibroblasts. This antifibrotic effect appeared to be independent of PPAR signaling and rather due to the inhibition of the TGF-ß1-induced Smad signaling. Lobeglitazone also blocked TGF-ß1-induced ROS generation and nicotinamide adenine dinucleotide phosphate oxidase (Nox) 4 transcription.CONCLUSION:
These findings indicate that lobeglitazone may be a promising therapeutic agent for corneal scarring. KEY MESSAGES.Palabras clave
Texto completo:
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Banco de datos:
MEDLINE
Asunto principal:
Pirimidinas
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Tiazolidinedionas
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Proteínas Smad
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Factor de Crecimiento Transformador beta1
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Fibroblastos
Límite:
Humans
Idioma:
En
Año:
2022
Tipo del documento:
Article