Proprotein convertase furin is a driver and potential therapeutic target in proliferative diabetic retinopathy

BACKGROUND: Furin converts inactive proproteins into bioactive forms. By activating proinflammatory and proangiogenic factors, furin might play a role in pathophysiology of proliferative diabetic retinopathy (PDR). METHODS: We studied vitreous samples from PDR and nondiabetic patients, epiretinal membranes from PDR patients, retinal microvascular endothelial cells (HRMECs), retinal Müller cells and rat retinas by ELISA, Western blot analysis, immunohistochemistry and immunofluorescence microscopy. We performed in vitro angiogenesis assays and assessed adherence of monocytes to HRMECs. RESULTS: Furin levels were significantly increased in PDR vitreous samples. In epiretinal membranes, immunohistochemistry analysis revealed furin expression in monocytes/macrophages, vascular endothelial cells and myofibroblasts. Furin was significantly upregulated in diabetic rat retinas. Hypoxia and TNF-α induced significant upregulation of furin in Müller cells and HRMECs. Furin induced upregulation of phospho-ERK1/2, p65 subunit of NF-κB, ADAM17 and MCP-1 in cultured Müller cells and phospho-ERK1/2 in cultured HRMECs and induced HRMECs migration. Treatment of monocytes with furin significantly increased their adhesion to HRMECs. Intravitreal administration of furin in normal rats induced significant upregulation of p65 subunit of NF-κB, phospho-ERK1/2 and ICAM-1 in the retina. Inhibition of furin with dec-CMK significantly decreased levels of MCP-1 in culture medium of Müller cells and HRMECs and significantly attenuated TNF-α-induced upregulation of p65 subunit of NF-κB, ICAM-1 and VCAM-1 in HRMECs. Dec-CMK significantly decreased adherence of monocytes to HRMECs and TNF-α-induced upregulation of adherence of monocytes to HRMECs. Treatment of HRMECs with dec-CMK significantly attenuated migration of HRMECs. CONCLUSIONS: Furin is a potential driver molecule of PDR-associated inflammation and angiogenesis.

Jaar van publicatie:2022

Toegankelijkheid:Closed