Epac1 regulates TLR4 signaling in the diabetic retinal vasculature.
Cytokine
; 144: 155576, 2021 08.
Article
en En
| MEDLINE
| ID: mdl-34020266
ABSTRACT
Toll-like receptor 4 (TLR4) polymorphisms occur in diabetic patients. Previous work showed that TLR4 is in the retina of diabetic mice, as well as in retinal endothelial cells (REC) and Müller cells. Since we have shown that exchange protein activated by cAMP 1 (Epac1) can reduce inflammatory mediators, we hypothesized that Epac1 would inhibit TLR4 signaling. We also hypothesized that direct TLR4 inhibition would protect the diabetic retina. Human REC in normal and high glucose were treated with an Epac1 agonist to explore the actions of Epac1 on TLR4 signaling in vitro. Subsequently, 2-month diabetic endothelial cell specific knockout mice for Epac1 (Cdh5Cre-Epac1) and Epac1 floxed mice retinas were used for Western blotting for TLR4 signaling pathways. We also used direct inhibition of TLR4 via Tak242 to investigate diabetes-induced changes in retinal permeability and neuronal loss in the mice. The Epac1 agonist reduced TLR4 signaling in REC grown in high glucose. TLR4 levels and both MyD88-dependent and -independent signaling pathways are increased in Cdh5Cre-Epac1 mice compared to Epac1 floxed mice. Tak242 reduced TLR4 signaling in diabetic mice and reduced diabetes-induced increases in permeability and cell loss in the ganglion cell layer in the Epac1 floxed and Cdh5Cre-Epac1 mice. In conclusion, Epac1 reduced TLR4 signaling in the retina and in REC. Direct inhibition of TLR4 was able to protect the retina against diabetes-induced changes in permeability and cell numbers in the ganglion cell layer.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Retina
/
Vasos Retinianos
/
Transducción de Señal
/
Factores de Intercambio de Guanina Nucleótido
/
Diabetes Mellitus Experimental
/
Retinopatía Diabética
/
Receptor Toll-Like 4
Límite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Cytokine
Asunto de la revista:
ALERGIA E IMUNOLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos