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- 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 reacquisition 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.

Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial-mesenchymal transition and fibrosis during peritoneal dialysis / Strippoli, Raffaele; Jesús, Loureiro; Vanessa, Moreno; Ignacio, Benedicto; María Luisa Pérez, Lozano; Olga, Barreiro; Teijo, Pellinen; Susana, Minguet; Miguel, Foronda; Maria Teresa, Osteso; Enrique, Calvo; Jesús, Vázquez; Manuel López, Cabrera; Miguel Angel del, Pozo. - In: EMBO MOLECULAR MEDICINE. - ISSN 1757-4676. - STAMPA. - 7:1(2015), pp. 102-123. [10.15252/emmm.201404127]

Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial-mesenchymal transition and fibrosis during peritoneal dialysis

STRIPPOLI, RAFFAELE;
2015

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- 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 reacquisition 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.
2015
Peritoneal dialysis; EMT; fibrosis; Caveolin-1; MEK-ERK1/2- pathway
01 Pubblicazione su rivista::01a Articolo in rivista
Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial-mesenchymal transition and fibrosis during peritoneal dialysis / Strippoli, Raffaele; Jesús, Loureiro; Vanessa, Moreno; Ignacio, Benedicto; María Luisa Pérez, Lozano; Olga, Barreiro; Teijo, Pellinen; Susana, Minguet; Miguel, Foronda; Maria Teresa, Osteso; Enrique, Calvo; Jesús, Vázquez; Manuel López, Cabrera; Miguel Angel del, Pozo. - In: EMBO MOLECULAR MEDICINE. - ISSN 1757-4676. - STAMPA. - 7:1(2015), pp. 102-123. [10.15252/emmm.201404127]
File allegati a questo prodotto
File Dimensione Formato  
Strippoli_Caveolin-1-deficiency.pdf

accesso aperto

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 4.13 MB
Formato Adobe PDF
4.13 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/639013
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 77
  • ???jsp.display-item.citation.isi??? 62
social impact