title: Tamoxifen ameliorates peritoneal membrane damage by blocking mesothelial to mesenchymal transition in peritoneal dialysis.
abstract: Mesothelial-to-mesenchymal transition (MMT) is an auto-regulated physiological process of tissue repair that in uncontrolled conditions such as peritoneal dialysis (PD) can lead to peritoneal fibrosis. The maximum expression of peritoneal fibrosis induced by PD fluids and other peritoneal processes is the encapsulating peritoneal sclerosis (EPS) for which no specific treatment exists. Tamoxifen, a synthetic estrogen, has successfully been used to treat retroperitoneal fibrosis and EPS associated with PD. Hence, we used in vitro and animal model approaches to evaluate the efficacy of Tamoxifen to inhibit the MMT as a trigger of peritoneal fibrosis. In vitro studies were carried out using omentum-derived mesothelial cells (MCs) and effluent-derived MCs. Tamoxifen blocked the MMT induced by transforming growth factor (TGF)-β1, as it preserved the expression of E-cadherin and reduced the expression of mesenchymal-associated molecules such as snail, fibronectin, collagen-I, α-smooth muscle actin, and matrix metalloproteinse-2. Tamoxifen-treatment preserved the fibrinolytic capacity of MCs treated with TGF-β1 and decreased their migration capacity. Tamoxifen did not reverse the MMT of non-epitheliod MCs from effluents, but it reduced the expression of some mesenchymal molecules. In mice PD model, we demonstrated that MMT progressed in parallel with peritoneal membrane thickness. In addition, we observed that Tamoxifen significantly reduced peritoneal thickness, angiogenesis, invasion of the compact zone by mesenchymal MCs and improved peritoneal function. Tamoxifen also reduced the effluent levels of vascular endothelial growth factor and leptin. These results demonstrate that Tamoxifen is a therapeutic option to treat peritoneal fibrosis, and that its protective effect is mediated via modulation of the MMT process.
authors: Centro de Biología Molecular-Severo Ochoa, CSIC-UAM, Cantoblanco, Madrid, Spain.
authors: Jesús
authors: J
authors: Loureiro
authors: Pilar
authors: P
authors: Sandoval
authors: Gloria
authors: G
authors: del Peso
authors: Guadalupe
authors: G
authors: Gónzalez-Mateo
authors: Vanessa
authors: V
authors: Fernández-Millara
authors: Beatríz
authors: B
authors: Santamaria
authors: Maria Auxiliadora
authors: MA
authors: Bajo
authors: José Antonio
authors: JA
authors: Sánchez-Tomero
authors: Gonzalo
authors: G
authors: Guerra-Azcona
authors: Rafael
authors: R
authors: Selgas
authors: Manuel
authors: M
authors: López-Cabrera
authors: Abelardo I
authors: AI
authors: Aguilera
mesh_terms: D000818:Animals; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D010537:Peritoneum / Q000098:blood supply / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D010641:Phenotype; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D053773:Transforming Growth Factor beta1; D013629:Tamoxifen
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