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BioMed Research International
Volume 2015 (2015), Article ID 989560, 15 pages
http://dx.doi.org/10.1155/2015/989560
Research Article

Rapamycin Protects from Type-I Peritoneal Membrane Failure Inhibiting the Angiogenesis, Lymphangiogenesis, and Endo-MT

1Centro de Biología Molecular-Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC), Cantoblanco, 28049 Madrid, Spain
2Departamento de Nefrologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, 05403-000 São Paulo, Brazil
3Aging and Inflammation Group, Instituto de Investigación Biomédica (INIBIC), 15006 A Coruña, Spain
4Departamento de Nefrología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), 28006 Madrid, Spain
5Departamento de Nefrología, Hospital Universitario La Paz & Instituto de Investigación Sanitaria la Paz (IdiPAZ), 28046 Madrid, Spain
6Departamento de Patología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), 28006 Madrid, Spain
7Unidad de Biología Molecular y Departamento de Nefrología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), 28006 Madrid, Spain

Received 23 May 2015; Revised 27 August 2015; Accepted 13 October 2015

Academic Editor: Janusz Witowski

Copyright © 2015 Guadalupe Tirma González-Mateo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Preservation of peritoneal membrane (PM) is essential for long-term survival in peritoneal dialysis (PD). Continuous presence of PD fluids (PDF) in the peritoneal cavity generates chronic inflammation and promotes changes of the PM, such as fibrosis, angiogenesis, and lymphangiogenesis. Mesothelial-to-mesenchymal transition (MMT) and endothelial-to-mesenchymal transition (Endo-MT) seem to play a central role in this pathogenesis. We speculated that Rapamycin, a potent immunosuppressor, could be beneficial by regulating blood and lymphatic vessels proliferation. We demonstrate that mice undergoing a combined PD and Rapamycin treatment (PDF + Rapa group) presented a reduced PM thickness and lower number of submesothelial blood and lymphatic vessels, as well as decreased MMT and Endo-MT, comparing with their counterparts exposed to PD alone (PDF group). Peritoneal water transport in the PDF + Rapa group remained at control level, whereas PD effluent levels of VEGF, TGF-β, and TNF-α were lower than in the PDF group. Moreover, the treatment of mesothelial cells with Rapamycin in vitro significantly decreased VEGF synthesis and selectively inhibited the VEGF-C and VEGF-D release when compared with control cells. Thus, Rapamycin has a protective effect on PM in PD through an antifibrotic and antiproliferative effect on blood and lymphatic vessels. Moreover, it inhibits Endo-MT and, at least partially, MMT.