TY - JOUR
T1 - Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial-mesenchymal transition and fibrosis during peritoneal dialysis
AU - Strippoli, Raffaele
AU - Loureiro, Jesús
AU - Moreno, Vanessa
AU - Benedicto, Ignacio
AU - Pérez Lozano, María Luisa
AU - Barreiro, Olga
AU - Pellinen, Teijo
AU - Minguet, Susana
AU - Foronda, Miguel
AU - Osteso, Maria Teresa
AU - Calvo, Enrique
AU - Vázquez, Jesús
AU - López Cabrera, Manuel
AU - del Pozo, Miguel Angel
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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-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. Synopsis: Peritoneal dialysis (PD) has major advantages vs. hemodialysis but leads to inflammation and injury to the PM. This study identifies MEK/ERK1/2 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. Peritoneal dialysis (PD) has major advantages vs. hemodialysis but leads to inflammation and injury to the PM. This study identifies MEK/ERK1/2 signaling as playing a central role in EMT and fibrosis occurring during PD, and caveolin-1 as an important regulator of these events.
AB - 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-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. Synopsis: Peritoneal dialysis (PD) has major advantages vs. hemodialysis but leads to inflammation and injury to the PM. This study identifies MEK/ERK1/2 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. Peritoneal dialysis (PD) has major advantages vs. hemodialysis but leads to inflammation and injury to the PM. This study identifies MEK/ERK1/2 signaling as playing a central role in EMT and fibrosis occurring during PD, and caveolin-1 as an important regulator of these events.
KW - Caveolin-1
KW - Epithelial-mesenchymal transition
KW - Fibrosis
KW - MEK-ERK1/2 pathway
KW - Peritoneal dialysis
UR - http://www.scopus.com/inward/record.url?scp=84925331493&partnerID=8YFLogxK
U2 - 10.15252/emmm.201404127
DO - 10.15252/emmm.201404127
M3 - Article
C2 - 25550395
AN - SCOPUS:84925331493
SN - 1757-4676
VL - 7
SP - 102
EP - 123
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 1
ER -