title: Interactions of DPP-4 and integrin β1 influences endothelial-to-mesenchymal transition.
abstract: Integrin β1 and dipeptidyl peptidase (DPP)-4 play roles in endothelial cell biology. Vascular endothelial growth factor (VEGF)-A inhibits endothelial-to-mesenchymal transition (EndMT) through VEGF-R2, but through VEGF-R1 promotes EndMT by reducing the bioavailability of VEGF-A. Here we tested whether DPP-4-integrin β1 interactions have a role in EndMT in the renal fibrosis of diabetic nephropathy. In streptozotocin-induced fibrotic kidneys in diabetic CD-1 mice, levels of endothelial DPP-4, integrin β1, and phospho-integrin β1 were all higher and associated with plasma cystatin C elevation. The DPP-4 inhibitor linagliptin ameliorated kidney fibrosis, reduced plasma cystatin C levels, and suppressed endothelial levels of DPP-4, integrin β1, and phospho-integrin β1. In cultured endothelial cells, DPP-4 and integrin β1 physically interacted. Suppression of DPP-4 by siRNA was associated with suppression of integrin β1 and vice versa. Knockdown of either integrin β1 or DPP-4 resulted in the silencing of TGF-β2-induced TGF-β receptor heterodimer formation, smad3 phosphorylation, and EndMT. DPP-4 negatively regulated endothelial viability signaling by VEGF-R2 suppression and VEGF-R1 induction in endothelial cells. Thus, DPP-4 and integrin β1 interactions regulate key endothelial cell signal transduction in both physiological and pathological conditions including EndMT. Hence, inhibiting DPP-4 may be a therapeutic target for treating kidney fibrosis in diabetes.
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Sen
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Swayam Prakash
authors.initials: SP
authors.lastname: Srivastava
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Kanasaki
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Jianhua
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Japan.|Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Munehiro
authors.initials: M
authors.lastname: Kitada
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nitta
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Takagi
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Japan.|Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Kanasaki
authors.affiliation: Department of Diabetology & Endocrinology, Kanazawa Medical University, Uchinada, Japan.|Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005355:Fibrosis; D007004:Hypoglycemic Agents / Q000494:pharmacology; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D000069476:Linagliptin / Q000494:pharmacology; D008297:Male; D051379:Mice; D010766:Phosphorylation; D034622:RNA Interference; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D014162:Transfection
chemical_list: D007004:Hypoglycemic Agents; D019012:Integrin beta1; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D000069476:Linagliptin; D040262:Receptors, Vascular Endothelial Growth Factor; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse
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