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Diabetologia

Erschienen in:

10.08.2018 | Article

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

verfasst von: Matthias Kolibabka, Nadine Dietrich, Thomas Klein, Hans-Peter Hammes

Erschienen in: Diabetologia | Ausgabe 11/2018

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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.

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Titel: Anti-angiogenic effects of the DPP-4 inhibitor linagliptin via inhibition of VEGFR signalling in the mouse model of oxygen-induced retinopathy
verfasst von: Matthias Kolibabka
Nadine Dietrich
Thomas Klein
Hans-Peter Hammes
Publikationsdatum: 10.08.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 11/2018
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-018-4701-4

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

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