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-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.
Highlights
Epithelial–mesenchymal transition (EMT) is a complex and stepwise process that occurs during embryonic development and tumor progression, and that has recently been described in chronic inflammatory and fibrogenic diseases (Kalluri & Weinberg, 2009; Thiery et al, 2009; Xu et al, 2009)
transforming growth factor (TGF)-b1 stimulation markedly reduced Cav1 levels in human primary mesothelial cells (MCs) (HPMCs) in a dose-dependent manner (Fig 1A), and this was paralleled by reduced expression of the epithelial marker E-cadherin and induction of the mesenchymal marker a-SMA
The results presented here establish a pivotal role for Cav1 in the EMT associated with Peritoneal dialysis (PD)-induced peritoneal membrane (PM) deterioration and demonstrate the effectiveness of inhibiting the MEK-ERK1/2 pathway in blocking or reversing these events
Summary
Epithelial–mesenchymal transition (EMT) is a complex and stepwise process that occurs during embryonic development and tumor progression, and that has recently been described in chronic inflammatory and fibrogenic diseases (Kalluri & Weinberg, 2009; Thiery et al, 2009; Xu et al, 2009). Cells acquire the ability to produce extracellular matrix components (ECM) such as fibronectin (FN) and collagen, as well as metalloproteinases and inflammatory, fibrogenic, and angiogenic factors. EMT is triggered by a complex interplay of extracellular signals, including ECM components and soluble growth factors and cytokines, such as members of the transforming growth factor (TGF)-b, fibroblast growth factor (FGF), epidermal growth factor (EGF), and hepatocyte growth factor (HGF). Germany §§Present address: Centre for Chronic Immunodeficiency CCI, University Clinics Freiburg and Medical Faculty, Albert-Ludwigs-University of Freiburg, Freiburg, Germany ¶¶Present address: MRC Centre for Regenerative Medicine, Edinburgh, UK.
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