Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial-mesenchymal transition and fibrosis during peritoneal dialysis
| Autor: | Miguel Foronda, Miguel A. del Pozo, Raffaele Strippoli, Maria Teresa Osteso, Jesús Loureiro, Susana Minguet, Olga Barreiro, Maria Luisa Lozano, Vanessa Moreno, Enrique Calvo, Teijo Pellinen, Manuel López Cabrera, Ignacio Benedicto, Jesús Vázquez |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Fundacio la Marato, Instituto de Salud Carlos III, Centro de Investigación Biomedica en Red - CIBERA97, Ministerio de Ciencia e Innovación (España), Fundación ProCNIC, Institute for Molecular Medicine Finland, Precision Systems Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
MAPK/ERK pathway
Pathology Caveolin 1 NF-KAPPA-B Smad Proteins epithelial–mesenchymal transition TRANSCRIPTIONAL ACTIVITY Mice 0302 clinical medicine Caveolin-1 Fibrosis Laminin Research Articles MEK-ERK1/2- pathway Mice Knockout Mitogen-Activated Protein Kinase 1 0303 health sciences Mitogen-Activated Protein Kinase 3 biology MEK‐ERK1/2 pathway MESOTHELIAL CELLS EMT TGF-BETA Epithelial-mesenchymal transition 3. Good health medicine.anatomical_structure 030220 oncology & carcinogenesis Molecular Medicine Peritoneum Corrigendum medicine.medical_specialty Epithelial-Mesenchymal Transition SCAFFOLDING DOMAIN MAP Kinase Signaling System education Peritoneal dialysis Transforming Growth Factor beta1 03 medical and health sciences E-CADHERIN EXPRESSION MEK-ERK1/2 pathway TGF beta signaling pathway medicine Animals Humans Epithelial–mesenchymal transition QUANTITATIVE PROTEOMICS 030304 developmental biology business.industry Mesenchymal stem cell fibrosis Epithelial Cells medicine.disease MAP KINASE PATHWAY ENDOTHELIAL GROWTH-FACTOR biology.protein Cancer research caveolin‐1 PULMONARY DEFECTS 3111 Biomedicine Snail Family Transcription Factors business Transcription Factors |
| Zdroj: | EMBO Molecular Medicine Repisalud Instituto de Salud Carlos III (ISCIII) Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid |
| Popis: | Peritoneal dialysis (PD) is a form of renal replacement therapy whose repeated use can alter dialytic function through induction of epithelial-mesenchymal transition (EMT) and fibrosis, eventually leading to PD discontinuation. The peritoneum from Cav1(-/-) mice showed increased EMT, thickness, and fibrosis. Exposure of Cav1(-/-) mice to PD fluids further increased peritoneal membrane thickness, altered permeability, and increased the number of FSP-1/cytokeratin-positive cells invading the sub-mesothelial stroma. High-throughput quantitative proteomics revealed increased abundance of collagens, FN, and laminin, as well as proteins related to TGF-beta activity in matrices derived from Cav1(-/-) cells. Lack of Cav1 was associated with hyperactivation of a MEK-ERK1/2-Snail-1 pathway that regulated the Smad2-3/Smad1-5-8 balance. Pharmacological blockade of MEK rescued E-cadherin and ZO-1 inter-cellular junction localization, reduced fibrosis, and restored peritoneal function in Cav1(-/-) mice. Moreover, treatment of human PD-patient-derived MCs with drugs increasing Cav1 levels, as well as ectopic Cav1 expression, induced re-acquisition of epithelial features. This study demonstrates a pivotal role of Cav1 in the balance of epithelial versus mesenchymal state and suggests targets for the prevention of fibrosis during PD. We thank Dr. Kurzchalia, Dr. Pol, and Dr. Lisanti for providing us MEFs from WT and Cav1-/- mice. We thank Dr. Valeria Caiolfa, head of CNIC Microscopy unit, and Elvira Arza and Antonio Manuel Santos Beneit for technical assistance. We thank Cecilia Battistelli and Marta Loureiro Lopez por technical assistance in molecular biology and proteomics, respectively. This work was supported by grants from the MINECO (Spanish Ministry of Economy and Competitivity) to MADP (SAF2008-02100, SAF2011-25047 and CONSOLIDER CSD2009-00016) and to MLC (SAF2010-21249 and SAF2013-47611R), and from Fundacio la Marato TV3 (674/C/2013) to MADP. Raffaele Strippoli was supported by a Rio Hortega Contract (Instituto de Salud Carlos III). Ignacio Benedicto was recipient of a CIBERehd fellowship (Spanish Ministry of Health and Consumer Affairs). Susana Minguet was supported by the Ramon y Cajal program (Spanish Ministry of Science and Innovation). Simon Bartlett (CNIC) provided editorial assistance. The CNIC is supported by MINECO and the Pro-CNIC Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí |
| Databáze: | OpenAIRE |
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