Abstract
Diabetic retinopathy (DR) develops due to hyperglycemia and inflammation-induced vascular disruptions in the retina with connexin43 expression patterns in the disease still debated. Here, the effects of hyperglycemia and inflammation on connexin43 expression in vitro in a mouse model of DR and in human donor tissues were evaluated. Primary human retinal microvascular endothelial cells (hRMECs) were exposed to high glucose (HG; 25 mM) or pro-inflammatory cytokines IL-1β and TNF-α (10 ng/mL each) or both before assessing connexin43 expression. Additionally, connexin43, glial fibrillary acidic protein (GFAP), and plasmalemma vesicular associated protein (PLVAP) were labeled in wild-type (C57BL/6), Akita (diabetic), and Akimba (DR) mouse retinas. Finally, connexin43 and GFAP expression in donor retinas with confirmed DR was compared to age-matched controls. Co-application of HG and cytokines increased connexin43 expression in hRMECs in line with results seen in mice, with no significant difference in connexin43 or GFAP expression in Akita but higher expression in Akimba compared to wild-type mice. On PLVAP-positive vessels, connexin43 was higher in Akimba but unchanged in Akita compared to wild-type mice. Connexin43 expression appeared higher in donor retinas with confirmed DR compared to age-matched controls, similar to the distribution seen in Akimba mice and correlating with the in vitro results. Although connexin43 expression seems reduced in diabetes, hyperglycemia and inflammation present in the pathology of DR seem to increase connexin43 expression, suggesting a causal role of connexin43 channels in the disease progression.
Highlights
Diabetic retinopathy (DR) is a chronic disease that develops due to hyperglycemia-induced vascular and inflammatory disruptions in the retina with the vascular pathology characterized by blood–retinal barrier leakage, pericyte loss, endothelial cell death, and neovascularization [1]
Previous studies have shown that the Akimba mouse uniquely displays features of advanced DR, most of which are not present in other models of the diseases [9,10]
Wisniewska-Kruk et al [10] showed that the Akimba mouse had reduced expression levels of various endothelial cell-specific markers such as von Willebrand factor and CD31 indicating a loss of blood vessels
Summary
Diabetic retinopathy (DR) is a chronic disease that develops due to hyperglycemia-induced vascular and inflammatory disruptions in the retina with the vascular pathology characterized by blood–retinal barrier leakage, pericyte loss, endothelial cell death, and neovascularization [1]. The Akimba mouse has been characterized as a model of advanced PDR [9,10] These studies, in combination with our own findings, suggest that a marked increase in connexin expression may be associated with the pathology of DR. Our findings support the hypothesis that DR is characterized by a combination of both hyperglycemic and inflammatory disease mechanisms They suggest that DR is associated with an increase in connexin expression that is distinct from the changes seen with diabetes or hyperglycemia alone. These findings highlight the need for a careful consideration of models used to study the retinal pathophysiology of DR especially when evaluating novel treatments for the condition
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