Vitamin D/vitamin D receptor protects intestinal barrier against colitis by positively regulating Notch pathway
ObjectiveVitamin D/Vitamin D receptor (VD/VDR) signaling and the Notch pathway are involved in intestinal barrier restoration in colitis; however, their relationship and underlying mechanism are largely unknown. Therefore, this study aimed to investigate the role and mechanism of VD/VDR and the Notc...
| Váldodahkkit: | , , , , , , |
|---|---|
| Materiálatiipa: | Artihkal |
| Giella: | English |
| Almmustuhtton: |
Frontiers Media S.A.
2024-07-01
|
| Ráidu: | Frontiers in Pharmacology |
| Fáttát: | |
| Liŋkkat: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1421577/full |
| _version_ | 1827179603300450304 |
|---|---|
| author | Yanni Li Yaoyu Guo Chong Geng Shuailing Song Wenjuan Yang Xiao Li Chunhui Wang |
| author_facet | Yanni Li Yaoyu Guo Chong Geng Shuailing Song Wenjuan Yang Xiao Li Chunhui Wang |
| author_sort | Yanni Li |
| collection | DOAJ |
| description | ObjectiveVitamin D/Vitamin D receptor (VD/VDR) signaling and the Notch pathway are involved in intestinal barrier restoration in colitis; however, their relationship and underlying mechanism are largely unknown. Therefore, this study aimed to investigate the role and mechanism of VD/VDR and the Notch pathways in intestinal barrier protection.MethodsGenetic Vdr knockout (VDR KO) and VD deficient (VDd) mice were established, and colitis was induced by feeding 2.5% dextran sodium sulfate (DSS) water. Mechanistic studies, including real-time PCR, immunofluorescence, Western blotting and dual-luciferase reporter assays, were performed on cultured Caco-2 cells and intestinal organoids.ResultsVD deficiency and VDR genetical KO increased the severity of DSS-induced colitis in mice, which presented a higher disease activity index score, increased intestinal permeability, and more severe intestinal histological damage than controls, accompanied by decreased and disrupted claudin-1 and claudin-3. Moreover, inhibition of Notch pathway by LY411,575 aggravated the severity of DSS-induced colitis and intestinal injury. In Caco-2 cells and intestinal organoids, the expression of Notch-1, N1ICD and Hes1 decreased upon downregulation or KO of VDR but increased upon paricalcitol (PAR, a VDR agonist) treatment. Meanwhile, PAR rescued claudin-1 and claudin-3 impairments that resulted from TNF-α exposure but failed to restore claudin-3 upon Notch inhibition. The dual-luciferase reporter assay further suggested that VD/VDR positively regulated the Notch signaling pathway by modulating Notch-1 transcription.ConclusionVD/VDR positively modulates Notch activation by promoting Notch-1 transcription to maintain intestinal tight junction integrity and barrier function. This highlights the VD/VDR-Notch pathway as a potential new therapeutic target for protecting the intestinal barrier against ulcerative colitis. |
| first_indexed | 2025-03-21T05:17:39Z |
| format | Article |
| id | doaj.art-22b5d6abceb64c1aa6b51e1f443df503 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2025-03-21T05:17:39Z |
| publishDate | 2024-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-22b5d6abceb64c1aa6b51e1f443df5032024-07-26T04:34:51ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-07-011510.3389/fphar.2024.14215771421577Vitamin D/vitamin D receptor protects intestinal barrier against colitis by positively regulating Notch pathwayYanni Li0Yaoyu Guo1Chong Geng2Shuailing Song3Wenjuan Yang4Xiao Li5Chunhui Wang6Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Gastroenterology, West China Hospital of Sichuan University, Chengdu, ChinaLaboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Gastroenterology, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Gastroenterology, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Gastroenterology, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Gastroenterology, West China Hospital of Sichuan University, Chengdu, ChinaObjectiveVitamin D/Vitamin D receptor (VD/VDR) signaling and the Notch pathway are involved in intestinal barrier restoration in colitis; however, their relationship and underlying mechanism are largely unknown. Therefore, this study aimed to investigate the role and mechanism of VD/VDR and the Notch pathways in intestinal barrier protection.MethodsGenetic Vdr knockout (VDR KO) and VD deficient (VDd) mice were established, and colitis was induced by feeding 2.5% dextran sodium sulfate (DSS) water. Mechanistic studies, including real-time PCR, immunofluorescence, Western blotting and dual-luciferase reporter assays, were performed on cultured Caco-2 cells and intestinal organoids.ResultsVD deficiency and VDR genetical KO increased the severity of DSS-induced colitis in mice, which presented a higher disease activity index score, increased intestinal permeability, and more severe intestinal histological damage than controls, accompanied by decreased and disrupted claudin-1 and claudin-3. Moreover, inhibition of Notch pathway by LY411,575 aggravated the severity of DSS-induced colitis and intestinal injury. In Caco-2 cells and intestinal organoids, the expression of Notch-1, N1ICD and Hes1 decreased upon downregulation or KO of VDR but increased upon paricalcitol (PAR, a VDR agonist) treatment. Meanwhile, PAR rescued claudin-1 and claudin-3 impairments that resulted from TNF-α exposure but failed to restore claudin-3 upon Notch inhibition. The dual-luciferase reporter assay further suggested that VD/VDR positively regulated the Notch signaling pathway by modulating Notch-1 transcription.ConclusionVD/VDR positively modulates Notch activation by promoting Notch-1 transcription to maintain intestinal tight junction integrity and barrier function. This highlights the VD/VDR-Notch pathway as a potential new therapeutic target for protecting the intestinal barrier against ulcerative colitis.https://www.frontiersin.org/articles/10.3389/fphar.2024.1421577/fulltight junctionintestinal barriervitamin Dvitamin D receptor (VDR)ulcerative colitisNotch pathway |
| spellingShingle | Yanni Li Yaoyu Guo Chong Geng Shuailing Song Wenjuan Yang Xiao Li Chunhui Wang Vitamin D/vitamin D receptor protects intestinal barrier against colitis by positively regulating Notch pathway Frontiers in Pharmacology tight junction intestinal barrier vitamin D vitamin D receptor (VDR) ulcerative colitis Notch pathway |
| title | Vitamin D/vitamin D receptor protects intestinal barrier against colitis by positively regulating Notch pathway |
| title_full | Vitamin D/vitamin D receptor protects intestinal barrier against colitis by positively regulating Notch pathway |
| title_fullStr | Vitamin D/vitamin D receptor protects intestinal barrier against colitis by positively regulating Notch pathway |
| title_full_unstemmed | Vitamin D/vitamin D receptor protects intestinal barrier against colitis by positively regulating Notch pathway |
| title_short | Vitamin D/vitamin D receptor protects intestinal barrier against colitis by positively regulating Notch pathway |
| title_sort | vitamin d vitamin d receptor protects intestinal barrier against colitis by positively regulating notch pathway |
| topic | tight junction intestinal barrier vitamin D vitamin D receptor (VDR) ulcerative colitis Notch pathway |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1421577/full |
| work_keys_str_mv | AT yannili vitamindvitamindreceptorprotectsintestinalbarrieragainstcolitisbypositivelyregulatingnotchpathway AT yaoyuguo vitamindvitamindreceptorprotectsintestinalbarrieragainstcolitisbypositivelyregulatingnotchpathway AT chonggeng vitamindvitamindreceptorprotectsintestinalbarrieragainstcolitisbypositivelyregulatingnotchpathway AT shuailingsong vitamindvitamindreceptorprotectsintestinalbarrieragainstcolitisbypositivelyregulatingnotchpathway AT wenjuanyang vitamindvitamindreceptorprotectsintestinalbarrieragainstcolitisbypositivelyregulatingnotchpathway AT xiaoli vitamindvitamindreceptorprotectsintestinalbarrieragainstcolitisbypositivelyregulatingnotchpathway AT chunhuiwang vitamindvitamindreceptorprotectsintestinalbarrieragainstcolitisbypositivelyregulatingnotchpathway |