Aflibercept regulates retinal inflammation elicited by high glucose via the PlGF/ERK pathway

Biochem Pharmacol. 2019 Oct:168:341-351. doi: 10.1016/j.bcp.2019.07.021. Epub 2019 Jul 25.

Abstract

Diabetic retinopathy (DR) is a secondary complication of diabetes. DR can cause irreversible blindness, and its pathogenesis is considered multifactorial. DR can progress from non-proliferative DR to proliferative DR, characterized by retinal neovascularization. The main cause of vision loss in diabetic patients is diabetic macular edema, caused by vessel leakage and blood retinal barrier breakdown. Currently, aflibercept is an anti-VEGF approved for diabetic macular edema. Aflibercept can bind several members of vascular permeability factors, namely VEGF-A, B, and PlGF. We analyzed the aflibercept-PlGF complex at molecular level, through an in silico approach. In order to explore the role of PlGF in DR, we treated primary human retinal endothelial cells (HRECs) and mouse retinal epithelial cells (RPEs) with aflibercept and an anti-PlGF antibody. We explored the hypothesis that aflibercept has anti-inflammatory action through blocking of PlGF signaling and the ERK axis in an in vitro and in vivo model of DR. Both aflibercept and the anti-PlGF antibody exerted protective effects on retinal cells, by inhibition of the ERK pathway. Moreover, aflibercept significantly decreased (p < 0.05) the expression of TNF-α in an in vitro and in vivo model of DR. Therefore, our data suggest that inhibition of PlGF signaling, or a selective blocking, may be useful in the management of early phases of DR when the inflammatory process is largely involved.

Keywords: Aflibercept; Diabetic retinopathy; PlGF; TNF-α; VEGF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Cells, Cultured
  • Computer Simulation
  • Endothelial Cells / drug effects
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Glucose / toxicity*
  • Humans
  • Inflammation / drug therapy*
  • Membrane Proteins / metabolism*
  • Mice
  • Models, Biological
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Domains
  • Rats
  • Receptors, Vascular Endothelial Growth Factor
  • Recombinant Fusion Proteins / pharmacology*
  • Retina / cytology
  • Retinal Diseases / drug therapy*

Substances

  • Angiogenesis Inhibitors
  • Membrane Proteins
  • PIGF protein, human
  • Recombinant Fusion Proteins
  • aflibercept
  • Receptors, Vascular Endothelial Growth Factor
  • Extracellular Signal-Regulated MAP Kinases
  • Glucose