title: 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.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.|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.
authors.forename: Choon-Soo
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Cardiovascular Center &Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.
authors.forename: Yun Gi
authors.initials: YG
authors.lastname: Kim
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.|Cardiovascular Center &Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.
authors.forename: Hyun-Jai
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.|Cardiovascular Center &Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.
authors.forename: Jonghanne
authors.initials: J
authors.lastname: Park
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, Korea.
authors.forename: Heewon
authors.initials: H
authors.lastname: Jeong
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.|Cardiovascular Center &Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.
authors.forename: Sang-Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Cardiovascular Center &Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.
authors.forename: Seung-Pyo
authors.initials: SP
authors.lastname: Lee
authors.affiliation: Innovative Research Institute for Cell Therapy, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.|Cardiovascular Center &Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.
authors.forename: Hyun-Jae
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, Korea.|Innovative Research Institute for Cell Therapy, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.|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.|Cardiovascular Center &Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Korea.
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D018920:Coculture Techniques; D003930:Diabetic Retinopathy / Q000139:chemically induced* / Q000503:physiopathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D054377:Chemokine CXCL12; D054873:Dipeptidyl-Peptidase IV Inhibitors; D019718:Receptors, CXCR4; D019061:src-Family Kinases; D000099152:Cadherin 5; C514936:CXCR4 protein, mouse