, Volume 61, Issue 11, pp 2412–2421 | Cite as

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

  • Matthias KolibabkaEmail author
  • Nadine Dietrich
  • Thomas Klein
  • Hans-Peter HammesEmail author



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.


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.


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).


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.


Angiogenesis DPP-4 GLP-1 Linagliptin Oxygen-induced retinopathy Proliferative retinopathy 



Dipeptidyl peptidase 4


Extracellular signal-regulated kinase


Glucagon-like peptide


Glucagon-like peptide 1 receptor


Hypoxia-inducible factor 1α


High-mobility group box 1


Human umbilical vascular endothelial cell


c-Jun N-terminal kinase


Mitogen-activated protein kinase


Neuropilin 1


Oxygen-induced retinopathy


Phosphoinositide 3-kinase


Quantitative PCR


Stromal cell-derived factor 1 α


Vascular endothelial growth factor


Vascular endothelial growth factor receptor


Contribution statement

MK, ND and HPH contributed to the conception and design of this study, acquisition, analysis and interpretation of data, reviewed the literature and critically drafted and revised the manuscript. TK contributed to acquisition, analysis and interpretation of data, reviewed the literature and critically drafted and revised the manuscript. All authors approved the final version of the manuscript. MK and HPH are responsible for the integrity of the work as a whole.


This study was funded and supported by Boehringer Ingelheim. MK is an associated member of the GRK1874 DIAMICOM, funded by the Deutsche Forschungsgemeinschaft.

Duality of interest

All authors declare that there is no duality of interest associated with this manuscript. TK is a full-time employee of Boehringer Ingelheim. Boehringer Ingelheim had no influence on the conception and design of this study, or on the decision to publish the results.

Supplementary material

125_2018_4701_MOESM1_ESM.pdf (140 kb)
ESM (PDF 139 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.5th Medical Department, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
  2. 2.Department of CardioMetabolic Diseases ResearchBoehringer Ingelheim PharmaBiberachGermany
  3. 3.European Center for Angioscience (ECAS), Medical Faculty MannheimHeidelberg UniversityMannheimGermany

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