title: Linagliptin but not Sitagliptin inhibited transforming growth factor-β2-induced endothelial DPP-4 activity and the endothelial-mesenchymal transition.
abstract: Dipeptidyl peptidase (DPP)-4 plays an important role in endothelial cell biology. We have shown that the DPP-4 inhibitor Linagliptin can inhibit the endothelial-mesenchymal transition (EndMT) and ameliorate diabetic kidney fibrosis associated with the suppression of DPP-4 protein levels via the induction of miR-29. The current study demonstrated that such effects of Linagliptin on endothelial cell profibrotic programs were drug-specific but not class effects. In the cell-free system, both Linagliptin and Sitagliptin inhibited recombinant DPP-4 activity in a concentration-dependent manner. Linagliptin can inhibit all of the following: DPP-4 activity and protein level, integrin β1 protein levels, EndMT, and DPP-4 3'UTR activity; Sitagliptin, however, inhibited none of these in the current study. Additionally, TGF-β2 induced both the induction of VEGF-R1 and the suppression of VEGF-R2 levels in endothelial cells, and both were inhibited by Linagliptin but not by Sitagliptin. miR-29, the miR that negatively regulates the 3'UTR of DPP-4 mRNA, was suppressed by TGF-β2 and restored by Linagliptin but not by Sitagliptin. Following the overexpression of pCMV-DPP-4-GFP and pCMV6-Myc-DPP-4 in endothelial cells, the proximity of Myc-DPP-4 and DPP-4-GFP was suppressed by Linagliptin but not by Sitagliptin, suggesting that only Linagliptin inhibited the homo-dimer formation of DPP-4 in endothelial cells; this difference in activity between the two gliptins could explain their diverse effects on endothelial cell biology. In conclusion, each of the DPP-4 inhibitors may have unique drug-specific effects.
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, 920-0293, Japan; Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, 920-0293, Ishikawa, Japan; The Department of Vascular and Thyroid Surgery, The First Affiliated Hospital of Sichuan Medical University, Luzhou, 646000, PR China.
authors.forename: Sen
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, 920-0293, Japan; Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, 920-0293, Ishikawa, Japan. Electronic address: kkanasak@kanazawa-med.ac.jp.
authors.forename: Keizo
authors.initials: K
authors.lastname: Kanasaki
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, 920-0293, Japan; Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, 920-0293, Ishikawa, Japan. Electronic address: koya0516@kanazawa-med.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
mesh_terms: D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000069476:Linagliptin / Q000008:administration & dosage*; D000068900:Sitagliptin Phosphate / Q000008:administration & dosage*; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D053781:Transforming Growth Factor beta2; D000069476:Linagliptin; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate
keywords: Dipeptidyl peptidase-4; Endothelial cell biology; Endothelial-mesenchymal transition