Caveolin‐1 deficiency induces a MEK ‐ ERK 1/2‐Snail‐1‐dependent epithelial–mesenchymal transition and fibrosis during peritoneal dialysis

Abstract 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 , th...

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Published in:EMBO molecular medicine 2015-01, Vol.7 (1), p.102-123
Main Authors: Strippoli, Raffaele, Loureiro, Jesús, Moreno, Vanessa, Benedicto, Ignacio, Pérez Lozano, María Luisa, Barreiro, Olga, Pellinen, Teijo, Minguet, Susana, Foronda, Miguel, Osteso, Maria Teresa, Calvo, Enrique, Vázquez, Jesús, López Cabrera, Manuel, del Pozo, Miguel Angel
Format: Article
Language:English
Subjects:
Caveolin
Caveolin-1
Collagen
Cytokeratin
Experiments
Extracellular signal-regulated kinase
Fibroblasts
Fibrosis
Growth factors
Kinases
Laminin
Localization
Membrane permeability
Mesenchyme
Metabolism
Peritoneal dialysis
Peritoneum
Proteomics
Smad2 protein
Stroma
Transcription factors
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Summary:Abstract 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 ‐β activity in matrices derived from Cav1 −/− cells. Lack of Cav1 was associated with hyperactivation of a MEK ‐ ERK 1/2‐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 MC s 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 . Synopsis image Peritoneal dialysis ( PD ) has major advantages vs. hemodialysis but leads to inflammation and injury to the PM . This study identifies MEK / ERK 1/2 signaling as playing a central role in EMT and fibrosis occurring during PD , and caveolin‐1 as an important regulator of these events. Caveolin‐1 (Cav1) limits the occurrence of EMT and fibrosis during peritoneal dialysis. Absence of Cav1 is associated to hyper‐activation of the MEK‐ERK‐Snail‐1 axis, which affects the SMAD2‐3/SMAD1‐5‐8 balance. MEK inhibition prevents EMT, fibrosis, and altered peritoneal membrane function in the peritoneum of Cav1 −/− mice undergoing peritoneal dialysis. Treatment of human peritoneal dialysis patient‐derived mesothelial cells with drugs increasing Cav1 levels, as well as ectopic Cav1 expression, induce re‐acquisition of epithelial features.
ISSN:1757-4676
1757-4684
DOI:10.15252/emmm.201404127