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Dipeptidyl peptidase 4 inhibitor sitagliptin protected against dextran sulfate sodium-induced experimental colitis by potentiating the action of GLP-2

文献类型：期刊论文

作者Ning, Meng-meng1; Yang, Wen-ji1,2; Guan, Wen-bo1,2; Gu, Yi-pei1; Feng, Ying1; Leng, Ying1,2
刊名ACTA PHARMACOLOGICA SINICA
出版日期2020-05-12
页码11
ISSN号1671-4083
关键词ulcerative colitis dextran sulfate sodium dipeptidyl peptidase 4 sitagliptin glucagon-like peptide-2 GLP-2(3-33) apoptosis proliferation
DOI10.1038/s41401-020-0413-7
通讯作者Leng, Ying(yleng@simm.ac.cn)
英文摘要Dipeptidyl peptidase 4 (DPP4), a ubiquitously expressed protease that cleaves off the N-terminal dipeptide from proline and alanine on the penultimate position, has important roles in many physiological processes. In the present study, experimental colitis was induced in mice receiving 3% dextran sulfate sodium (DSS) in drinking water. We found that mice with DSS-induced colitis had significantly increased intestinal DPP activity and decreased serum DPP activity, suggesting a probable correlation of DPP4 with experimental colitis. Then, we investigated whether sitagliptin, a specific DPP4 inhibitor could protect against DSS-induced colitis. We showed that oral administration of single dose of sitagliptin (30 mg/kg) on D7 remarkably inhibited DPP enzyme activity in both serum and intestine of DSS-induced colitic mice. Repeated administration of sitagliptin (10, 30 mg/kg, bid, from D0 to D8) significantly ameliorated DSS-induced colitis, including reduction of disease activity index (DAI) and body weight loss, improvement of histological score and colon length. Sitagliptin administration dose-dependently increased plasma concentrations of active form of GLP-1 and colonic expression of GLP-2R. Co-administration of GLP-2R antagonist GLP-2(3-33) (500 mu g/kg, bid, sc) abolished the protective effects of sitagliptin in DSS-induced colitic mice. Moreover, sitagliptin administration significantly decreased the ratio of apoptotic cells and increased the ratio of proliferative cells in colon epithelium of DSS-induced colitic mice, and this effect was also blocked by GLP-2(3-33). Taken together, our results demonstrate that sitagliptin could attenuate DSS-induced experimental colitis and the effects can be attributed to the enhancement of GLP-2 action and the subsequent protective effects on intestinal barrier by inhibiting epithelial cells apoptosis and promoting their proliferation. These findings suggest sitagliptin as a novel therapeutic approach for the treatment of ulcerative colitis.
WOS关键词COLONIC EPITHELIUM ; IV ; MECHANISMS ; EXPRESSION ; MORTALITY ; SURVIVAL ; CD26
资助项目National Natural Science Foundation of China[81872922]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者NATURE PUBLISHING GROUP
WOS记录号WOS:000532186400002
源URL[http://119.78.100.183/handle/2S10ELR8/280292]  
专题新药研究国家重点实验室
通讯作者Leng, Ying
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Ning, Meng-meng,Yang, Wen-ji,Guan, Wen-bo,et al. Dipeptidyl peptidase 4 inhibitor sitagliptin protected against dextran sulfate sodium-induced experimental colitis by potentiating the action of GLP-2[J]. ACTA PHARMACOLOGICA SINICA,2020:11.
APA Ning, Meng-meng,Yang, Wen-ji,Guan, Wen-bo,Gu, Yi-pei,Feng, Ying,&Leng, Ying.(2020).Dipeptidyl peptidase 4 inhibitor sitagliptin protected against dextran sulfate sodium-induced experimental colitis by potentiating the action of GLP-2.ACTA PHARMACOLOGICA SINICA,11.
MLA Ning, Meng-meng,et al."Dipeptidyl peptidase 4 inhibitor sitagliptin protected against dextran sulfate sodium-induced experimental colitis by potentiating the action of GLP-2".ACTA PHARMACOLOGICA SINICA (2020):11.

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来源：上海药物研究所

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