Tamoxifen exerts anti-peritoneal fibrosis effects by inhibiting H19-activated VEGFA transcription

• DOI: 10.1186/s12967-023-04470-3
• Publication Date: 2023-09-11T10:02:16Z
• Authors: Tingting Zhao; Zhengyu Sun; Xueli Lai; Hongtao Lu; Lulu Liu; Shuangxi Li; Ji-hang Yuan; Zhiyong Guo
• Keywords: Vascular Endothelial Growth Factor A; Peritoneal fibrosis; Research; Estrogen receptor 1; R; Long non-coding RNA H19; Fibrosis; 3. Good health; Mice; Tamoxifen; Glucose; Vascular endothelial growth factor A; Dialysis Solutions; Medicine; Animals; Humans; RNA; Peritoneum

Abstract Background Peritoneal dialysis (PD) remains limited due to failure caused by peritoneal fibrosis. Tamoxifen (TAM), an inhibitor of estrogen receptor 1 (ESR1), has been reported treat fibrosis, but the underlying mechanism unknown. In this study, we sought explore whether tamoxifen played anti-fibrotic role affecting transcription factor ESR1. Methods ESR1 expression was detected in human peritoneum. Mice were daily intraperitoneally injected with 4.25% glucose PD dialysate containing 40 mM methylglyoxal for 2 weeks establish PD-induced administrated gavage, at dose 10 mg/kg. Chromatin immunoprecipitation (ChIP) and dual‐luciferase reporter assay performed validate bound H19 promoter. Gain-of-function loss-of-function experiments investigate biological roles on mesothelial-mesenchymal transition (MMT) mesothelial cells (HPMCs). Intraperitoneal injection nanomaterial-wrapped 2′- O -Me-modified small interfering RNA applied suppress mouse pull-down assays demonstrated binding between p300. Exfoliated obtained from effluent analyze correlations (or H19) solute transfer rate (PSTR). Results increased significantly peritoneum after long-term exposure dialysate. treatment ameliorated high glucose-induced MMT HPMCs, improved ultrafiltration rate, decreased PSTR reduced level decreasing . Depletion reversed pro-fibrotic effect while ectopic exacerbated fibrotic pathological changes. siRNAs targeting mitigated PD-related fibrosis mice. (RIP) results delineated that activated VEGFA p300 promoter inducing histone acetylation promising targets predict function. Conclusions High via activating cells, transcribed binds cofactor activate Targeting ESR1/H19/VEGFA pathway provided new hope patients undergoing dialysis. Graphic