The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin ameliorates retinal endothelial cell dysfunction triggered by inflammation

Biomed Pharmacother. 2018 Jun:102:833-838. doi: 10.1016/j.biopha.2018.03.144. Epub 2018 Apr 5.

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.

Keywords: Angiogenesis; DPP-4 inhibitor; Endothelial permeability; Inflammation; Migration; Retinal endothelial cells; Sitagliptin.

MeSH terms

  • Animals
  • Capillaries / growth & development
  • Cattle
  • Cell Membrane Permeability / drug effects
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology*
  • Inflammation / drug therapy*
  • Inflammation / pathology*
  • Morphogenesis / drug effects
  • Neovascularization, Physiologic / drug effects
  • Retina / pathology*
  • Sitagliptin Phosphate / pharmacology
  • Sitagliptin Phosphate / therapeutic use*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Tumor Necrosis Factor-alpha
  • Sitagliptin Phosphate