Identification of connexin43 in diabetic retinopathy and its downregulation by O-GlcNAcylation to inhibit the activation of glial cells

• Published in: Biochimica et biophysica acta. General subjects Vol. 1865; no. 10; p. 129955
• Main Authors: Liu, Guodong, Wang, Yanliang, Keyal, Khusbu, Feng, Le, Zhang, Conghui, Wang, Hao, Wang, Fang
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2021
• Subjects: animals; Connexin43; Diabetic retinopathy; fluorescent antibody technique; Glial fibrillary acidic protein; hyperglycemia; O-GlcNAcylation; therapeutics; Diabetic retinopathy; BRB; Cx43; Glial fibrillary acidic protein; HRECs; STAT3; STZ; O-GlcNAcylation; Connexin43; GFAP; PDR
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2021.129955

Despite advances in the treatments of diabetic complications, proliferative diabetic retinopathy (PDR) still remains a major cause leading to visual loss, mainly because of the lack of pathological mechanisms and complicated protein expressions in vivo. Current study aimed to investigate the patterns of connexin43 (Cx43) changes and the possible interactions with O-GlcNAcylation in DR. Clinical samples of vitreous and fibrovascular membranes were acquired from PDR patients during pars plana vitrectomy. Brown Norway rats were used to build diabetic animal models; to investigate the effects of O-GlcNAcylation on Cx43 expressions, total retinal O-GlcNAcylation was changed by intravitreal injections. Levels of protein expressions were examined by immunofluorescence staining and western blot. Our results revealed increased Cx43 expressions in a vessel-shape pattern followed by the distribution of glial fibrillary acidic protein (GFAP) in diabetic fibrovascular membranes. Similarly, Cx43 and GFAP expressions were elevated in PDR vitreous and diabetic animal retinas. Retinal O-GlcNAcylation was effectively regulated by intravitreal injections, and the increase of Cx43 and GFAP was significantly suppressed by O-GlcNAcylation inhibition under hyperglycemia conditions. We systemically proved the changes of Cx43 with different retinal cells, and reported the effective methods to regulate retinal O-GlcNAcylation by intravitreal injections, and clearly illustrated the downregulated effects of O-GlcNAcylation inhibition on Cx43 and GFAP expressions. General significance: Targeting connexin43 in glial cells reveals a novel mechanism to understand the formation of diabetic fibrovascular membranes and offers a potential therapeutic strategy to interfere the development of PDR. •Our study proved the specific changes of Cx43 within different cells correlated with diabetic retinopathy.•For the first time to report the methods to regulate retinal O-GlcNAcylation through intravitreal injections.•The significant effects of O-GlcNAcylation inhibition on Cx43 and GFAP expressions provided possible  treatments for PDR.