Abstract
In proliferative diabetic retinopathy (PDR), activated Müller glial cells (MGCs) exhibit increased motility and a fibroblast-like proliferation phenotype that contribute to the formation of fibrovascular membrane. In this study, we investigated the capacity of high glucose (HG) to regulate the expression of cell surface receptors that may participate in the proinflammatory responses of MGCs. We found that MGCs express a G-protein coupled chemoattractant receptor formyl peptide receptor 2 (Fpr2) and fibroblast growth factor receptor 1 (FGFR1), which mediated MGC migration and proliferation in response to corresponding ligands. HG upregulated Fpr2 through an NF-κB pathway in MGCs, increased the activation of MAPKs coupled to Fpr2 and FGFR1, which also further enhanced the production of vascular endothelial growth factor by MGCs in the presence of HG. In vivo, Fpr2 was more highly expressed by retina MGCs of diabetic mice and the human counterpart FPR2 was detected in the retina MGCs in fibrovascular membrane of PDR patients. To support the potential pathological relevance of Fpr2, an endogenous Fpr2 agonist cathelin-related antimicrobial peptide was detected in mouse MGCs and the retina, which was upregulated by HG. These results suggest that Fpr2, together with FGFR1, may actively participate in the pathogenesis of PDR thus may be considered as one of the potential therapeutic targets.
Highlights
Diabetic retinopathy (DR) is a severe complication of diabetes and the leading cause of blindness
We report that high glucose (HG) upregulates the function of fibroblast growth factor receptor 1 (FGFR1) on mouse Müller glial cells (MGCs) and enhances the expression and function of a chemoattractant G-protein-coupled chemoattractant receptors (GPCRs), formyl peptide receptor 2 (FPR2, Fpr2 in mice) to exacerbate MGC chemotaxis, proliferation and production of vascular endothelial growth factor (VEGF), contributing to the progression of proliferative DR (PDR)
We first investigated the expression of Fpr2 and FGFR1 in MGCs
Summary
Diabetic retinopathy (DR) is a severe complication of diabetes and the leading cause of blindness. Many abnormalities seen in the retina of diabetes patients are associated with inflammation [1]. Anti-inflammatory therapies significantly reduce the progression of DR in animal models. DR is staged based on levels of severity to mild, moderate, and severe nonproliferative. DR, followed by advanced proliferative DR (PDR). In PDR, proliferative neovasculature and fibrovascular tissues extend from the retina into the vitreous. Tractional forces originating within these tissues cause vitreous hemorrhage, retinal scars, and tractional retinal detachment, leading to irreversible vision loss. The origin and the process of fibrovascular membrane formation remain unclear, it is believed that inflammation linked to hyperglycemia is the basis for DR [2]
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