Anti-angiogenic effects of the DPP-4 inhibitor linagliptin via inhibition of VEGFR signalling in the mouse model of oxygen-induced retinopathy

Diabetologia. 2018 Nov;61(11):2412-2421. doi: 10.1007/s00125-018-4701-4. Epub 2018 Aug 10.

Abstract

Aims/hypothesis: Linagliptin has protective effects on the retinal neurovascular unit but, in proliferative retinopathy, dipeptidyl peptidase 4 (DPP-4) inhibition could be detrimental. The aim of this study was to assess the effect of linagliptin on ischaemia-induced neovascularisation of the retina.

Methods: C57BL/6J and glucagon-like peptide 1 (GLP-1) receptor (Glp1r)-/- mice were subjected to a model of oxygen-induced retinopathy (OIR). Both strains were subcutaneously treated with linagliptin from postnatal days 12 to 16. Non-injected OIR and non-exposed mice served as controls. Capillary proliferations and systemic levels of active GLP-1 were quantified. The effects of linagliptin on vascular endothelial growth factor (VEGF)-induced downstream signalling were assessed in human umbilical vein endothelial cells (HUVECs) using western blot for retinal phosphorylated extracellular signal-regulated kinase (ERK)1/2 and retinal gene expression analyses.

Results: Linagliptin treatment led to an increase in active GLP-1 and a decreased number of neovascular nuclei in OIR mice vs controls (-30%, p < 0.05). As the reduction in neovascularisation was similar in both C57BL/6J and Glp1r-/- mice, the anti-angiogenic effects of linagliptin were independent of GLP-1R status. The expression of Vegf (also known as Vegfa) and Hif1a was increased in C57BL/6J OIR mice upon linagliptin treatment (three- vs 1.5-fold, p < 0.05, p < 0.01, respectively). In HUVECs, linagliptin inhibited VEGF-induced increases in mitogen-activated protein kinase (MAPK)/ERK (-67%, p < 0.001) and MAPK/c-Jun N-terminal kinase (JNK) (-13%, p < 0.05) pathway activities. In the retinas of C57BL/6J mice, p-ERK1/2 levels were significantly reduced upon linagliptin treatment (-47%, p < 0.05).

Conclusions/interpretation: Systemic treatment with linagliptin demonstrated GLP-1R-independent anti-angiogenic effects mediated by an inhibition of VEGF receptor downstream signalling. The specific effects of linagliptin on diabetic retinopathy are of potential benefit for individuals with diabetes, independent of metabolic effects.

Keywords: Angiogenesis; DPP-4; GLP-1; Linagliptin; Oxygen-induced retinopathy; Proliferative retinopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetic Retinopathy / drug therapy*
  • Diabetic Retinopathy / etiology
  • Diabetic Retinopathy / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Disease Models, Animal
  • Glucagon-Like Peptide 1 / genetics
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Linagliptin / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxygen / adverse effects*
  • Retina / metabolism
  • Retina / pathology
  • Retinal Neovascularization / drug therapy
  • Retinal Neovascularization / genetics
  • Retinal Neovascularization / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Glucagon-Like Peptide-1 Receptor
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Vascular Endothelial Growth Factor A
  • Linagliptin
  • Glucagon-Like Peptide 1
  • Oxygen