Linagliptin but not Sitagliptin inhibited transforming growth factor-β2-induced endothelial DPP-4 activity and the endothelial-mesenchymal transition
Linagliptin but not Sitagliptin inhibited transforming growth factor-β2-induced endothelial DPP-4 activity and the endothelial-mesenchymal transition
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DOI：
10.1016/j.bbrc.2016.01.154
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发表时间：
2016-02-26
影响因子：
3.1
通讯作者：
Koya, Daisuke
中科院分区：
文献类型：
--
作者：
Shi, Sen;Kanasaki, Keizo;Koya, Daisuke
二肽基肽酶（DPP）-4在内皮细胞生物学中起重要作用。我们已经证明，DPP-4抑制剂利格列汀可以抑制内皮-间质转化（EndMT），并通过诱导miR-29改善与DPP-4蛋白水平抑制相关的糖尿病肾纤维化。当前研究表明，利格列汀对内皮细胞促纤维化程序的影响是药物特异性的，而不是类效应。在无细胞系统中，利格列汀和西格列汀均以浓度依赖性方式抑制重组DPP-4活性。利格列汀可抑制以下所有方面：DPP-4活性和蛋白水平、整合素β 1蛋白水平、EndMT和DPP-4 3 'UTR活性;然而，在本研究中，西格列汀对这些均无抑制作用。此外，TGF-β 2可诱导内皮细胞中VEGF-R1的诱导和VEGF-R2水平的抑制，利格列汀可抑制这两种作用，而西格列汀则不能。miR-29（负调节DPP-4 mRNA 3 'UTR的miR）被TGF-β 2抑制，并被利格列汀恢复，但不被西格列汀恢复。在内皮细胞中过表达pCMV-DPP-4-GFP和pCMV 6-Myc-DPP-4后，Myc-DPP-4和DPP-4-GFP的接近性受到利格列汀的抑制，但西格列汀没有，这表明只有利格列汀抑制了内皮细胞中DPP-4的同源二聚体形成;两种格列汀之间的活性差异可以解释其对内皮细胞生物学的不同影响。总之，每种DPP-4抑制剂可能具有独特的药物特异性作用。(C)2016作者爱思唯尔公司出版
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 beta 1 protein levels, EndMT, and DPP-4 3'UTR activity; Sitagliptin, however, inhibited none of these in the current study. Additionally, TGF-beta 2 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-beta 2 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. (C) 2016 The Authors. Published by Elsevier Inc.