title: Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor.
abstract: BACKGROUND
  Advanced glycation end products (AGEs) and receptor RAGE interaction play a role in diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is a potential therapeutic target for type 2 diabetes. However, the role of DPP-4 in AGE-induced endothelial cell (EC) damage remains unclear.
  
  
  METHODS
  In this study, we investigated the effects of DPP-4 on reactive oxygen species (ROS) generation and RAGE gene expression in ECs. We further examined whether an inhibitor of DPP-4, linagliptin inhibited AGE-induced soluble DPP-4 production, ROS generation, RAGE, intercellular adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1) gene expression in ECs.
  
  
  RESULTS
  DPP-4 dose-dependently increased ROS generation and RAGE gene expression in ECs, which were prevented by linagliptin. Mannose 6-phosphate (M6P) and antibodies (Ab) raised against M6P/insulin-like growth factor II receptor (M6P/IGF-IIR) completely blocked the ROS generation in DPP-4-exposed ECs, whereas surface plasmon resonance revealed that DPP-4 bound to M6P/IGF-IIR at the dissociation constant of 3.59 x 10⁻⁵ M. AGEs or hydrogen peroxide increased soluble DPP-4 production by ECs, which was prevented by N-acetylcysteine, RAGE-Ab or linagliptin. Linagliptin significantly inhibited the AGE-induced ROS generation, RAGE, ICAM-1 and PAI-1 gene expression in ECs.
  
  
  CONCLUSIONS
  The present study suggests that AGE-RAGE-induced ROS generation stimulates the release of DPP-4 from ECs, which could in turn act on ECs directly via the interaction with M6P/IGF-IIR, further potentiating the deleterious effects of AGEs. The blockade by linagliptin of positive feedback loop between AGE-RAGE axis and DPP-4 might be a novel therapeutic target for vascular injury in diabetes.
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan. shoichi@med.kurume-u.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishibashi
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.forename: Sayaka
authors.initials: S
authors.lastname: Maeda
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Higashimoto
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
mesh_terms: D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D019899:Paracrine Communication; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D017127:Glycation End Products, Advanced; C573420:ICAM1 protein, human; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D017527:Receptor, IGF Type 2; D011971:Receptors, Immunologic; C051321:SERPINE1 protein, human; C034304:cation-dependent mannose-6-phosphate receptor; D018799:Intercellular Adhesion Molecule-1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4