title: Rapamycin Protects from Type-I Peritoneal Membrane Failure Inhibiting the Angiogenesis, Lymphangiogenesis, and Endo-MT.
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.
authors.affiliation: Centro de Biología Molecular-Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC), Cantoblanco, 28049 Madrid, Spain.
authors.forename: Guadalupe Tirma
authors.identifier: 0000-0002-8144-904X
authors.initials: GT
authors.lastname: González-Mateo
authors.affiliation: Departamento de Nefrologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, 05403-000 São Paulo, Brazil.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Aguirre
authors.affiliation: Aging and Inflammation Group, Instituto de Investigación Biomédica (INIBIC), 15006 A Coruña, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Loureiro
authors.affiliation: Departamento de Nefrologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, 05403-000 São Paulo, Brazil.
authors.forename: Hugo
authors.initials: H
authors.lastname: Abensur
authors.affiliation: Centro de Biología Molecular-Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC), Cantoblanco, 28049 Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sandoval
authors.affiliation: Departamento de Nefrología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), 28006 Madrid, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Sánchez-Tomero
authors.affiliation: Departamento de Nefrología, Hospital Universitario La Paz & Instituto de Investigación Sanitaria la Paz (IdiPAZ), 28046 Madrid, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: del Peso
authors.affiliation: Departamento de Patología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), 28006 Madrid, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Jiménez-Heffernan
authors.affiliation: Centro de Biología Molecular-Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC), Cantoblanco, 28049 Madrid, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Ruiz-Carpio
authors.affiliation: Departamento de Nefrología, Hospital Universitario La Paz & Instituto de Investigación Sanitaria la Paz (IdiPAZ), 28046 Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Selgas
authors.affiliation: Centro de Biología Molecular-Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC), Cantoblanco, 28049 Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Cabrera
authors.affiliation: Unidad de Biología Molecular y Departamento de Nefrología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), 28006 Madrid, Spain.
authors.forename: Abelardo
authors.initials: A
authors.lastname: Aguilera
authors.affiliation: Centro de Biología Molecular-Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC), Cantoblanco, 28049 Madrid, Spain.
authors.forename: Georgios
authors.initials: G
authors.lastname: Liappas
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D042583:Lymphangiogenesis / Q000187:drug effects*; D008567:Membranes, Artificial; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D008567:Membranes, Artificial; D020123:Sirolimus