Abstract
Background The impairment of the inner blood–retinal barrier (iBRB) increases the pathological development of diabetic retinopathy (DR), a severe complication in diabetic patients. Identifying approaches to preserving iBRB integrity and function is a significant challenge in DR. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly discovered adipokine and a vital biomarker, predicting DR severity. We sought to determine whether and how CTRP3 affects the pathological development of non-proliferative diabetic retinopathy (NPDR). Methods To clarify the pathophysiologic progress of the blood–retinal barrier in NPDR and explore its potential mechanism, a mouse Type 2 diabetic model of diabetic retinopathy was used. The capillary leakage was assessed by confocal microscope with fluorescent-labeled protein in vivo. Furthermore, the effect of CTRP3 on the inner blood–retinal barrier (iBRB) and its molecular mechanism was clarified. Results The results demonstrated that CTRP3 protects iBRB integrity and resists the vascular permeability induced by DR. Mechanistically, the administration of CTRP3 activates the AMPK signaling pathway and enhances the expression of Occludin and Claudin-5 (tight junction protein) in vivo and in vitro. Meanwhile, CTRP3 improves the injury of human retinal endothelial cells (HRMECs) induced by high glucose/high lipids (HG/HL), and its protective effects are AMPK-dependent. Conclusions In summary, we report, for the first time, that CTRP3 prevents diabetes-induced retinal vascular permeability via stabilizing the tight junctions of the iBRB and through the AMPK-dependent Occludin/Claudin-5 signaling pathway, thus critically affecting the development of NPDR.
Highlights
Administration of Globular Domain CTRP3 (gCTRP3) reversed those changes in the retinal tissue in the diabetic retinopathy (DR) model. These effects were blocked by Compound C administration (Figure 6A–C). These results suggest that C1q/tumor necrosis factor-related protein-3 (CTRP3) maintained the barrier function of inner blood–retinal barrier (iBRB) in DR by preventing the diabetes-induced Occludin and Claudin-5/tight junctions protein disruption, via AMPK-dependent signaling
We report that AMPK activation in the retina was inhibited in diabetes-induced non-proliferative diabetic retinopathy (NPDR), suppressing the crucial molecules Occludin and Claudin-5 in iBRB
We have recently demonstrated that circulating CTRP3 may serve as a valuable biomarker in the screening of diabetic retinopathy in patients, as it is inversely associated with DR severity [12]
Summary
Despite improvements in clinical patient care, risk factor identification and public health awareness of diabetes are still lacking well-noted research. A large population of diabetes patients progress to diabetic retinopathy (DR), a problematic complication of diabetes, causing blindness, especially in developed countries [1]. Diabetic retinopathy is considered a microvascular complication of endothelial dysfunction, characterized by damage of the blood–retinal barrier (BRB), and neovascularization [2]. The BRB is composed of two distinct barriers; the outer BRB, consisting of retinal pigment epithelium, and the inner BRB (iBRB), which is formed by the tight junctions between neighboring retinal capillary endothelial cells, and regulates transportation across retinal capillaries. The loss of iBRB occurs in the early stages of diabetes [3,4] (non-proliferative stage, NPDR)
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