Tamoxifen exerts anti-peritoneal fibrosis effects by inhibiting H19-activated VEGFA transcription
Abstract Background Peritoneal dialysis (PD) remains limited due to dialysis failure caused by peritoneal fibrosis. Tamoxifen (TAM), an inhibitor of estrogen receptor 1 (ESR1), has been reported to treat fibrosis, but the underlying mechanism remains unknown. In this study, we sought to explore whet...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-023-04470-3 |
| _version_ | 1797556880454713344 |
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| author | Tingting Zhao Zhengyu Sun Xueli Lai Hongtao Lu Lulu Liu Shuangxi Li Ji-hang Yuan Zhiyong Guo |
| author_facet | Tingting Zhao Zhengyu Sun Xueli Lai Hongtao Lu Lulu Liu Shuangxi Li Ji-hang Yuan Zhiyong Guo |
| author_sort | Tingting Zhao |
| collection | DOAJ |
| description | Abstract Background Peritoneal dialysis (PD) remains limited due to dialysis failure caused by peritoneal fibrosis. Tamoxifen (TAM), an inhibitor of estrogen receptor 1 (ESR1), has been reported to treat fibrosis, but the underlying mechanism remains unknown. In this study, we sought to explore whether tamoxifen played an anti-fibrotic role by affecting transcription factor ESR1. Methods ESR1 expression was detected in the human peritoneum. Mice were daily intraperitoneally injected with 4.25% glucose PD dialysate containing 40 mM methylglyoxal for 2 weeks to establish PD-induced peritoneal fibrosis. Tamoxifen was administrated by daily gavage, at the dose of 10 mg/kg. Chromatin immunoprecipitation (ChIP) and dual‐luciferase reporter assay were performed to validate ESR1 bound H19 promoter. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of H19 on the mesothelial-mesenchymal transition (MMT) of human peritoneal mesothelial cells (HPMCs). Intraperitoneal injection of nanomaterial-wrapped 2′-O-Me-modified small interfering RNA was applied to suppress H19 in the mouse peritoneum. RNA immunoprecipitation and RNA pull-down assays demonstrated binding between H19 and p300. Exfoliated peritoneal cells were obtained from peritoneal dialysis effluent to analyze the correlations between ESR1 (or H19) and peritoneal solute transfer rate (PSTR). Results ESR1 was increased significantly in the peritoneum after long-term exposure to PD dialysate. Tamoxifen treatment ameliorated high glucose-induced MMT of HPMCs, improved ultrafiltration rate, and decreased PSTR of mouse peritoneum. Tamoxifen reduced the H19 level by decreasing the ESR1 transcription of H19. Depletion of H19 reversed the pro-fibrotic effect of high glucose while ectopic expression of H19 exacerbated fibrotic pathological changes. Intraperitoneal injection of nanomaterial-wrapped 2′-O-Me-modified siRNAs targeting H19 mitigated PD-related fibrosis in mice. RNA immunoprecipitation (RIP) and RNA pull-down results delineated that H19 activated VEGFA expression by binding p300 to the VEGFA promoter and inducing histone acetylation of the VEGFA promoter. ESR1 and H19 were promising targets to predict peritoneal function. Conclusions High glucose-induced MMT of peritoneal mesothelial cells in peritoneal dialysis via activating ESR1. In peritoneal mesothelial cells, ESR1 transcribed the H19 and H19 binds to transcription cofactor p300 to activate the VEGFA. Targeting ESR1/H19/VEGFA pathway provided new hope for patients undergoing peritoneal dialysis. Graphic Abstract |
| first_indexed | 2024-03-10T17:09:19Z |
| format | Article |
| id | doaj.art-c82ae251f5e24cb9869685e93a295e78 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-10T17:09:19Z |
| publishDate | 2023-09-01 |
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| series | Journal of Translational Medicine |
| spelling | doaj.art-c82ae251f5e24cb9869685e93a295e782023-11-20T10:44:11ZengBMCJournal of Translational Medicine1479-58762023-09-0121111710.1186/s12967-023-04470-3Tamoxifen exerts anti-peritoneal fibrosis effects by inhibiting H19-activated VEGFA transcriptionTingting Zhao0Zhengyu Sun1Xueli Lai2Hongtao Lu3Lulu Liu4Shuangxi Li5Ji-hang Yuan6Zhiyong Guo7Department of Nephrology, First Affiliated Hospital of Naval Medical University, Shanghai Changhai HospitalDepartment of Nephrology, First Affiliated Hospital of Naval Medical University, Shanghai Changhai HospitalDepartment of Nephrology, First Affiliated Hospital of Naval Medical University, Shanghai Changhai HospitalDepartment of Nutrition, Naval Medical UniversityDepartment of Nephrology, First Affiliated Hospital of Naval Medical University, Shanghai Changhai HospitalDepartment of Nephrology, First Affiliated Hospital of Naval Medical University, Shanghai Changhai HospitalDepartment of Medical Genetics, Naval Medical UniversityDepartment of Nephrology, First Affiliated Hospital of Naval Medical University, Shanghai Changhai HospitalAbstract Background Peritoneal dialysis (PD) remains limited due to dialysis failure caused by peritoneal fibrosis. Tamoxifen (TAM), an inhibitor of estrogen receptor 1 (ESR1), has been reported to treat fibrosis, but the underlying mechanism remains unknown. In this study, we sought to explore whether tamoxifen played an anti-fibrotic role by affecting transcription factor ESR1. Methods ESR1 expression was detected in the human peritoneum. Mice were daily intraperitoneally injected with 4.25% glucose PD dialysate containing 40 mM methylglyoxal for 2 weeks to establish PD-induced peritoneal fibrosis. Tamoxifen was administrated by daily gavage, at the dose of 10 mg/kg. Chromatin immunoprecipitation (ChIP) and dual‐luciferase reporter assay were performed to validate ESR1 bound H19 promoter. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of H19 on the mesothelial-mesenchymal transition (MMT) of human peritoneal mesothelial cells (HPMCs). Intraperitoneal injection of nanomaterial-wrapped 2′-O-Me-modified small interfering RNA was applied to suppress H19 in the mouse peritoneum. RNA immunoprecipitation and RNA pull-down assays demonstrated binding between H19 and p300. Exfoliated peritoneal cells were obtained from peritoneal dialysis effluent to analyze the correlations between ESR1 (or H19) and peritoneal solute transfer rate (PSTR). Results ESR1 was increased significantly in the peritoneum after long-term exposure to PD dialysate. Tamoxifen treatment ameliorated high glucose-induced MMT of HPMCs, improved ultrafiltration rate, and decreased PSTR of mouse peritoneum. Tamoxifen reduced the H19 level by decreasing the ESR1 transcription of H19. Depletion of H19 reversed the pro-fibrotic effect of high glucose while ectopic expression of H19 exacerbated fibrotic pathological changes. Intraperitoneal injection of nanomaterial-wrapped 2′-O-Me-modified siRNAs targeting H19 mitigated PD-related fibrosis in mice. RNA immunoprecipitation (RIP) and RNA pull-down results delineated that H19 activated VEGFA expression by binding p300 to the VEGFA promoter and inducing histone acetylation of the VEGFA promoter. ESR1 and H19 were promising targets to predict peritoneal function. Conclusions High glucose-induced MMT of peritoneal mesothelial cells in peritoneal dialysis via activating ESR1. In peritoneal mesothelial cells, ESR1 transcribed the H19 and H19 binds to transcription cofactor p300 to activate the VEGFA. Targeting ESR1/H19/VEGFA pathway provided new hope for patients undergoing peritoneal dialysis. Graphic Abstracthttps://doi.org/10.1186/s12967-023-04470-3Peritoneal fibrosisTamoxifenEstrogen receptor 1Long non-coding RNA H19Vascular endothelial growth factor A |
| spellingShingle | Tingting Zhao Zhengyu Sun Xueli Lai Hongtao Lu Lulu Liu Shuangxi Li Ji-hang Yuan Zhiyong Guo Tamoxifen exerts anti-peritoneal fibrosis effects by inhibiting H19-activated VEGFA transcription Journal of Translational Medicine Peritoneal fibrosis Tamoxifen Estrogen receptor 1 Long non-coding RNA H19 Vascular endothelial growth factor A |
| title | Tamoxifen exerts anti-peritoneal fibrosis effects by inhibiting H19-activated VEGFA transcription |
| title_full | Tamoxifen exerts anti-peritoneal fibrosis effects by inhibiting H19-activated VEGFA transcription |
| title_fullStr | Tamoxifen exerts anti-peritoneal fibrosis effects by inhibiting H19-activated VEGFA transcription |
| title_full_unstemmed | Tamoxifen exerts anti-peritoneal fibrosis effects by inhibiting H19-activated VEGFA transcription |
| title_short | Tamoxifen exerts anti-peritoneal fibrosis effects by inhibiting H19-activated VEGFA transcription |
| title_sort | tamoxifen exerts anti peritoneal fibrosis effects by inhibiting h19 activated vegfa transcription |
| topic | Peritoneal fibrosis Tamoxifen Estrogen receptor 1 Long non-coding RNA H19 Vascular endothelial growth factor A |
| url | https://doi.org/10.1186/s12967-023-04470-3 |
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