C1q/TNF-Related Protein 3 Prevents Diabetic Retinopathy via AMPK-Dependent Stabilization of Blood–Retinal Barrier Tight Junctions

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.

The Role of Adipokines in the Pathogenesis of Psoriasis

“…Interestingly, CTRP3 was found to promote the secretion of leptin, adiponectin, and visfatin in 3T3-L1 adipocytes [ 227 ]. Furthermore, several studies on different cell types and with animal models demonstrated that CTRP3 may promote AMPK phosphorylation and SIRT1 enhancement [ 228 , 229 , 230 , 231 , 232 ]. To date, little is known about the role of CTRP3 in the development of psoriasis.…”

Diabetic retinopathy: Involved cells, biomarkers, and treatments

“…The Nrf2/HO–1 pathway is a target of CTRP3, and suppressor of cytokine signaling 3 is a direct target of miR-455–5p ( Chen et al, 2019 ; Zhang and He, 2019 ). Furthermore, CTRP3 mediates iBRB compatibility and resists vascular permeability induced by DR through the AMPK-dependent occludin/claudin –5 signaling pathway ( Yan et al, 2022 ).…”

Response of Human Retinal Microvascular Endothelial Cells to Influenza A (H1N1) Infection and the Underlying Molecular Mechanism

“…The outer layer is primarily composed of retinal pigment epithelial cells and their tight junctions, whereas the inner layer is composed of retinal vascular endothelial cells and their tight junctions. 48 , 49 This barrier prevents substances from leaking out of the blood vessels and controls the entry and exit of immune cells. However, research has demonstrated that various conditions, such as ischemia, hypoxia, inflammation, infection, diabetes, and hypertension, can lead to the detriment of endothelial cells and subsequently disrupt the integrity of the blood-retinal barrie.…”