Dipeptidyl Peptidase-4 Inhibitor Increases Vascular Leakage in Retina through VE-cadherin Phosphorylation View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-07-06

AUTHORS

Choon-Soo Lee, Yun Gi Kim, Hyun-Jai Cho, Jonghanne Park, Heewon Jeong, Sang-Eun Lee, Seung-Pyo Lee, Hyun-Jae Kang, Hyo-Soo Kim

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. More... »

PAGES

29393

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/srep29393

DOI

http://dx.doi.org/10.1038/srep29393

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1024144012

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27381080


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33 schema:description 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.
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43 DPP4 inhibitors
44 SDF
45 SDF-1α
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47 Src
48 Src/VE-cadherin
49 VE-cadherin
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51 actual leakage
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53 angiogenesis
54 blockers
55 cell junctions
56 cell-derived factor-1α
57 cells
58 data highlight safety issues
59 diabetic patients
60 diabetic retinopathy
61 diabetic retinopathy model
62 dipeptidyl peptidase-4 inhibitors
63 disruption
64 ear
65 effect
66 endothelial cells
67 endothelial monolayers
68 endothelial permeability
69 factor-1α
70 fundamental pathophysiology
71 glucose levels
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73 human endothelial cells
74 images
75 immuno-fluorescence images
76 inducer
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80 junction
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82 levels
83 miles
84 model
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88 pathophysiology
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91 peptidase-4 inhibitors
92 permeability
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96 receptor of SDF
97 receptors
98 retina
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