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

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Fibrosis* ; Peritoneum* ; Tamoxifen*/pharmacology; Animals ; Humans ; Mice ; Dialysis Solutions ; Glucose ; RNA ; Vascular Endothelial Growth Factor A/genetics

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.
(© 2023. BioMed Central Ltd., part of Springer Nature.)

J Am Soc Nephrol. 2011 Sep;22(9):1682-95. (PMID: 21742730)
J Transl Med. 2021 Jun 30;19(1):283. (PMID: 34193173)
Mol Cell. 2021 Apr 15;81(8):1682-1697.e7. (PMID: 33651988)
Blood. 2009 May 28;113(22):5568-74. (PMID: 19336759)
Nefrologia. 2012;32(6):707-14. (PMID: 23169353)
Stem Cell Res Ther. 2018 Apr 19;9(1):109. (PMID: 29673400)
Cell Rep. 2018 Aug 14;24(7):1722-1729. (PMID: 30110629)
Oncogene. 1999 Aug 5;18(31):4460-73. (PMID: 10442637)
PLoS One. 2013 Apr 23;8(4):e61165. (PMID: 23637793)
Mol Cancer. 2014 Apr 28;13:91. (PMID: 24775564)
Cell. 2014 Mar 27;157(1):77-94. (PMID: 24679528)
Int J Mol Sci. 2019 Nov 16;20(22):. (PMID: 31744097)
Circulation. 2020 Oct 13;142(15):1464-1484. (PMID: 32698630)
Int J Mol Sci. 2023 Mar 17;24(6):. (PMID: 36982834)
N Engl J Med. 2021 Nov 4;385(19):1786-1795. (PMID: 34731538)
Hepatology. 2019 Oct;70(4):1317-1335. (PMID: 30985008)
Nephrol Dial Transplant. 2005 Jul;20(7):1336-49. (PMID: 15814533)
Nat Rev Nephrol. 2013 Jul;9(7):419-29. (PMID: 23670085)
Int J Mol Sci. 2020 Jun 10;21(11):. (PMID: 32532126)
Cell. 1996 Nov 29;87(5):953-9. (PMID: 8945521)
Nature. 2018 Oct;562(7728):538-544. (PMID: 30323286)
Ageing Res Rev. 2019 Jul;52:17-31. (PMID: 30954650)
J Biol Chem. 2016 Jun 17;291(25):13271-85. (PMID: 27129775)
Biol Reprod. 2020 Feb 14;102(2):327-338. (PMID: 31511857)
J Am Soc Nephrol. 2021 Oct;32(10):2408-2415. (PMID: 34321252)
Autoimmunity. 2020 Feb;53(1):1-7. (PMID: 31646913)
PLoS One. 2013 Apr 09;8(4):e60776. (PMID: 23585849)
Am J Physiol Renal Physiol. 2020 Feb 1;318(2):F338-F353. (PMID: 31841386)
Biosci Rep. 2019 May 2;39(5):. (PMID: 30948500)
Nephrol Dial Transplant. 2006 Jul;21 Suppl 2:ii2-7. (PMID: 16825254)
Hepatology. 2019 Nov;70(5):1658-1673. (PMID: 31063660)
Int J Mol Sci. 2020 May 04;21(9):. (PMID: 32375307)
Cell. 2017 Jan 12;168(1-2):135-149.e22. (PMID: 28086087)
Nat Cell Biol. 2012 Jun 10;14(7):659-65. (PMID: 22684254)
Am J Respir Crit Care Med. 2019 Nov 15;200(10):1246-1257. (PMID: 31291549)
Ren Fail. 2020 Nov;42(1):932-943. (PMID: 32909490)
Hepatology. 2017 Sep;66(3):869-884. (PMID: 28271527)
J Am Soc Nephrol. 2018 Jan;29(1):268-282. (PMID: 29046343)
J Pathol. 2022 Oct;258(2):164-178. (PMID: 35792675)
J Am Soc Nephrol. 2012 Jan;23(1):37-48. (PMID: 22052053)

Keywords: Estrogen receptor 1; Long non-coding RNA H19; Peritoneal fibrosis; Tamoxifen; Vascular endothelial growth factor A

0 (Dialysis Solutions)
IY9XDZ35W2 (Glucose)
63231-63-0 (RNA)
0 (Vascular Endothelial Growth Factor A)
094ZI81Y45 (Tamoxifen)

Date Created: 20230911 Date Completed: 20230928 Latest Revision: 20231121

20231215

PMC10494369

10.1186/s12967-023-04470-3

37697303