Activation of the 5-hydroxytryptamine 4 receptor ameliorates tight junction barrier dysfunction in the colon of type 1 diabetic mice  

作　　者：Shasha Hu Yueting Kou Xiaochen Liu Weifang Rong Hongxiu Han Guohua Zhang 

机构地区：[1]Department of Anatomy and Physiology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [2]Department of Pathology,Tongji Hospital,Tongji University,Shanghai 200065,China

出　　处：《Acta Biochimica et Biophysica Sinica》2023年第12期1874-1883,共10页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the National Natural Science Foundation of China (No.81770355 to G.Z.);the Natural Science Foundation of Shanghai (No.23ZR1457700 to H.H.);the Shanghai Tongi Hospital (No.GJPY2123 to H.H.);the Innovative Research Team of High-Level Local Universities in Shanghai (No.SHSMU-ZDCX20211102 to G.Z).

摘　　要：Hyperglycemia drives dysfunction of the intestinal barrier.5-Hydroxytryptaine 4 receptor(5-HT4R)agonists have been considered therapeutics for constipation in clnic.However,the roles of 5-HT4R activation in mucosa should be fully realized.Here,we investigate the effects of 5-HT4R activation on diabetes-induced disruption of the tight junction(TJ)barrier in the colon.Not surprisingly,the TJ barrier in diabetic mice with or without 5-HT4R is tremendously destroyed,as indicated by increased serum fluorescein isothiocyanate(FITC)-dextran and decreased transepithelial electrical resistance(TER).Simultaneously,decreased expressions of TJ proteins are shown in both wild-type(WT)and 5-HT4R knockout(KO)mice with diabetes.Notably,chronic treatment with intraperitoneal injection of a 5-HT4R agonist in WT mice with diabetes repairs the TJ barrier and promotes TJ protein expressions,including occludin,claudin-1 and ZO-1,in the colon,whereas a 5-HT4R agonist does not improve TJ barrier function or TJ protein expressions in 5-HT4R KO mice with diabetes.Furthermore,stimulation of 5-HT4R inhibits diabetesinduced upregulation of myosin light chain kinase(MLCK),Rho-associated coiled coil protein kinase 1(ROCK1),and phosphorylated myosin light chain(p-MLC),which are key molecules that regulate TJ integrity,in the colonic mucosa of WT mice.However,such action induced by a 5-HT4R agonist is not observed in 5-HT4R KO mice with diabetes.These findings indicate that 5-HT4R activation may restore TJ integrity by inhibiting the expressions of MLCK,ROCK1 and p-MLC,improving epithelial barrier function in diabetes.

关 键 词：5-HT4R DIABETES tight junction barrier MLCK ROCK1 

分 类 号：R587.1[医药卫生—内分泌] R574[医药卫生—内科学]