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Updated: Mar 26, 2026

Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
Published on: August 3, 2018
Linagliptin but not Sitagliptin inhibited transforming growth factor-β2-induced endothelial DPP-4 activity and the
Sen Shi1, Keizo Kanasaki2, Daisuke Koya2
1Department 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.
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.
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