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Updated: Feb 12, 2026
A Microphysiological System to Study Leukocyte-Endothelial Cell Interaction during Inflammation
Published on: December 9, 2021
The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin ameliorates retinal endothelial cell dysfunction triggered
Andreia Gonçalves1, Luísa Almeida1, Ana Paula Silva1
1Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC.IBILI Consortium, University of Coimbra, Coimbra, Portugal.
Abstract:
Diabetic retinopathy is considered a low-grade chronic inflammatory disease and several inflammatory molecules, including tumor necrosis factor (TNF)-α, are known to play a major role in the degeneration of retinal capillaries. Previous studies have reported that sitagliptin, a DPP-4 inhibitor, prevents the increase in blood-retinal barrier (BRB) permeability and inhibits the tight junction disassembly induced by diabetes.
Aim:
Our goal was to investigate whether sitagliptin is able to prevent retinal endothelial cells (EC) dysfunction triggered by the pro-inflammatory cytokine TNF-α.
Main Methods:
The effects of TNF-α and/or sitagliptin on primary cultures of bovine retinal EC were tested. The EC monolayer permeability was analyzed by using 70 kDa rhodamine isothiocyanate (RITC) dextran. The cellular distribution profile of claudin-5 was examined by immunofluorescence staining, and DPP-4 activity was evaluated by using a fluorogenic substrate. Cell viability was assessed by MTT assay, and cell proliferation by the BrdU incorporation assay. Retinal EC migration and angiogenesis were evaluated by a scratch assay and a capillary tube formation in matrigel assay, respectively.
Key Findings:
TNF-α increased the permeability of EC monolayer and induced the loss of claudin-5 immunostaining at the cell borders. This impairment was associated with decreased migration and capillary morphogenesis of retinal EC. Sitagliptin was unable to prevent the effect of TNF-α on EC permeability. However, it decreased DPP-4 activity in bovine retinal EC exposed to TNF-α, without affecting cell viability. Moreover, sitagliptin enhanced the migration and capillary morphogenesis in bovine retinal EC challenged with TNF-α.
Significance:
These results suggest that sitagliptin is able to positively modulate vascular EC function under conditions of retinal inflammation.
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