Tamoxifen ameliorates peritoneal membrane damage by blocking mesothelial to mesenchymal transition in peritoneal dialysis
EntityUAM. Departamento de Medicina
PublisherPublic Library of Science
10.1371/journal.pone.0061165Plos One 8.4 (2013): e61165
Funded byThis work was supported by grant SAF2010-21249 from the ‘‘Ministerio de Economia y Competitividad’’ to MLC and by grant S2010/BMD-2321 from ‘‘Comunidad Autónoma de Madrid’’ to MLC and RS. This work was also partially supported by grants PI 09/0776 from ‘‘Fondo de Investigaciones Sanitarias’’ to AA, and RETICS 06/0016 (REDinREN, Fondos FEDER, EU) to RS
ProjectComunidad de Madrid. S2010/BMD-2321/FIBROTEAM
SubjectsEpithelial-Mesenchymal Transition; Fibrinolysis; Inbred C57BL; Peritoneal Dialysis; Tamoxifen; Medicina
Rights© 2013 Loureiro et al.
Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.
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
Google Scholar:Loureiro, Jesús - Sandoval, Pilar - Del Peso, Gloria D. - González-Mateo, Guadalupe Tirma - Fernández-Millara, Vanessa - Santamaría, Beatríz - Bajo Rubio, María Auxiliadora - Sánchez-Tomero, José Antonio - Guerra-Azcona, Gonzalo - Selgas Gutiérrez, Rafael - López-Cabrera, Manuel - Aguilera, Abelardo I.
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