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

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.

• 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
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 29393 (07 06 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27381080 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• CXCR4 protein, mouse
• Cadherins
• Chemokine CXCL12
• Dipeptidyl-Peptidase IV Inhibitors
• Receptors, CXCR4
• cadherin 5
• src-Family Kinases

Topics

• Animals
• Antigens, CD (metabolism)
• Cadherins (metabolism)
• Capillary Permeability (drug effects)
• Chemokine CXCL12 (metabolism)
• Coculture Techniques
• Diabetic Retinopathy (chemically induced, physiopathology)
• Dipeptidyl-Peptidase IV Inhibitors (adverse effects, pharmacology)
• Disease Models, Animal
• Endothelial Cells (cytology, drug effects, metabolism)
• Endothelium, Vascular (drug effects)
• Human Umbilical Vein Endothelial Cells
• Humans
• Intercellular Junctions (drug effects)
• Mice
• Phosphorylation
• Receptors, CXCR4 (metabolism)
• Retina (cytology, drug effects)
• Signal Transduction (drug effects)
• src-Family Kinases (metabolism)