2024-03-28T15:51:55Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/55272023-08-31T08:01:55Zcom_20.500.12105_2152com_20.500.12105_2051com_20.500.12105_2144com_20.500.12105_2145col_20.500.12105_2153col_20.500.12105_2146
00925njm 22002777a 4500
dc
Strippoli, Raffaele
author
Loureiro, Jesus
author
Moreno, Vanessa
author
Benedicto, Ignacio
author
Perez Lozano, Maria Luisa
author
Barreiro, Olga
author
Pellinen, Teijo
author
Minguet, Susana
author
Foronda, Miguel
author
Osteso, Maria Teresa
author
Calvo, Enrique
author
Vazquez, Jesus
author
Lopez Cabrera, Manuel
author
del Pozo, Miguel Angel
author
2015
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.
EMBO Mol Med. 2015; 7(1):102-23
1757-4676
http://hdl.handle.net/20.500.12105/5527
25550395
1757-4684
EMBO Molecular Medicine
Caveolin-1
Epithelial-mesenchymal transition
Fibrosis
MEK-ERK1/2 pathway
Peritoneal dialysis
ENDOTHELIAL GROWTH-FACTOR
E-CADHERIN EXPRESSION
MAP KINASE PATHWAY
NF-KAPPA-B
MESOTHELIAL CELLS
TGF-BETA
TRANSCRIPTIONAL ACTIVITY
QUANTITATIVE PROTEOMICS
SCAFFOLDING DOMAIN
PULMONARY DEFECTS
Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial-mesenchymal transition and fibrosis during peritoneal dialysis