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Sci Rep. 2016 Jul 6;6:29393. doi: 10.1038/srep29393.

Dipeptidyl Peptidase-4 Inhibitor Increases Vascular Leakage in Retina through VE-cadherin Phosphorylation.

Lee CS1,2,3, Kim YG4, Cho HJ1,2,4, Park J1,2,4, Jeong H1, Lee SE1,2,4, Lee SP4, Kang HJ2,4, Kim HS1,2,3,4.

Author information

1
National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, Korea.
2
Innovative Research Institute for Cell Therapy, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.
3
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul, Korea.
4
Cardiovascular Center &Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.

Abstract

The inhibitors of CD26 (dipeptidyl peptidase-4; DPP4) have been widely prescribed to control glucose level in diabetic patients. DPP4-inhibitors, however, accumulate stromal cell-derived factor-1α (SDF-1α), a well-known inducer of vascular leakage and angiogenesis both of which are fundamental pathophysiology of diabetic retinopathy. The aim of this study was to investigate the effects of DPP4-inhibitors on vascular permeability and diabetic retinopathy. DPP4-inhibitor (diprotin A or sitagliptin) increased the phosphorylation of Src and vascular endothelial-cadherin (VE-cadherin) in human endothelial cells and disrupted endothelial cell-to-cell junctions, which were attenuated by CXCR4 (receptor of SDF-1α)-blocker or Src-inhibitor. Disruption of endothelial cell-to-cell junctions in the immuno-fluorescence images correlated with the actual leakage of the endothelial monolayer in the transwell endothelial permeability assay. In the Miles assay, vascular leakage was observed in the ears into which SDF-1α was injected, and this effect was aggravated by DPP4-inhibitor. In the model of retinopathy of prematurity, DPP4-inhibitor increased not only retinal vascularity but also leakage. Additionally, in the murine diabetic retinopathy model, DPP4-inhibitor increased the phosphorylation of Src and VE-cadherin and aggravated vascular leakage in the retinas. Collectively, DPP4-inhibitor induced vascular leakage by augmenting the SDF-1α/CXCR4/Src/VE-cadherin signaling pathway. These data highlight safety issues associated with the use of DPP4-inhibitors.

PMID:
27381080
PMCID:
PMC4933943
DOI:
10.1038/srep29393
[Indexed for MEDLINE]
Free PMC Article

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