scholarly journals Mesenchymal Conversion of Mesothelial Cells Is a Key Event in the Pathophysiology of the Peritoneum during Peritoneal Dialysis

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Manuel López-Cabrera
Keyword(s):  
Peritoneal Dialysis ◽  
Epithelial To Mesenchymal Transition ◽  
Degradation Products ◽  
Therapeutic Option ◽  
Functional Decline ◽  
Mesothelial Cells ◽  
Peritoneal Membrane ◽  
Pharmacological Agents ◽  
Membrane Function ◽  
Mesenchymal Transition

Peritoneal dialysis (PD) is a therapeutic option for the treatment of end-stage renal disease and is based on the use of the peritoneum as a semipermeable membrane for the exchange of toxic solutes and water. Long-term exposure of the peritoneal membrane to hyperosmotic PD fluids causes inflammation, loss of the mesothelial cells monolayer, fibrosis, vasculopathy, and angiogenesis, which may lead to peritoneal functional decline. Peritonitis may further exacerbate the injury of the peritoneal membrane. In parallel with these peritoneal alterations, mesothelial cells undergo an epithelial to mesenchymal transition (EMT), which has been associated with peritoneal deterioration. Factors contributing to the bioincompatibility of classical PD fluids include the high content of glucose/glucose degradation products (GDPs) and their acidic pH. New generation low-GDPs-neutral pH fluids have improved biocompatibility resulting in better preservation of the peritoneum. However, standard glucose-based fluids are still needed, as biocompatible solutions are expensive for many potential users. An alternative approach to preserve the peritoneal membrane, complementary to the efforts to improve fluid biocompatibility, is the use of pharmacological agents protecting the mesothelium. This paper provides a comprehensive review of recent advances that point to the EMT of mesothelial cells as a potential therapeutic target to preserve membrane function.

scholarly journals Methylglyoxal Induced Basophilic Spindle Cells with Podoplanin at the Surface of Peritoneum in Rat Peritoneal Dialysis Model

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Ichiro Hirahara ◽  
Hideki Sato ◽  
Toshimi Imai ◽  
Akira Onishi ◽  
Yoshiyuki Morishita ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Structural Changes ◽  
Epithelial To Mesenchymal Transition ◽  
Degradation Products ◽  
Smooth Muscle Actin ◽  
Functional Decline ◽  
Intraperitoneal Administration ◽  
Mesothelial Cells ◽  
Mesenchymal Transition ◽  
Spindle Cells

Peritoneal dialysis (PD) is a common treatment for patients with reduced or absent renal function. Long-term PD leads to peritoneal injury with structural changes and functional decline. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis (EPS), which is a serious complication of PD. In order to carry out PD safely, it is important to define the mechanism of progression of peritoneal injury and EPS. We prepared rat models of peritoneal injury by intraperitoneal administration of glucose degradation products, such as methylglyoxal (MGO) or formaldehyde (FA), chlorhexidine gluconate (CG), and talc. In rats treated with MGO, peritoneal fibrous thickening with the appearance of basophilic spindle cells with podoplanin, cytokeratin, andα-smooth muscle actin at the surface of the peritoneum was observed. These cells may have been derived from mesothelial cells by epithelial-to-mesenchymal transition. In FA- or CG-treated rats, the peritoneum was thickened, and mesothelial cells were absent at the surface of the peritoneum. The CG- or MGO-treated rats presented with a so-called abdominal cocoon. In the talc-treated rats, extensive peritoneal adhesion and peritoneal thickening were observed. MGO-induced peritoneal injury model may reflect human histopathology and be suitable to analyze the mechanism of progression of peritoneal injury and EPS.

scholarly journals Effluent Tenascin-C Levels Reflect Peritoneal Deterioration in Peritoneal Dialysis: MAJOR IN PD Study

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Ichiro Hirahara ◽  
Eiji Kusano ◽  
Toshimi Imai ◽  
Yoshiyuki Morishita ◽  
Makoto Inoue ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Structural Changes ◽  
Epithelial To Mesenchymal Transition ◽  
Functional Decline ◽  
Major Complication ◽  
Mesothelial Cells ◽  
Matrix Metalloproteinase 2 ◽  
Mesenchymal Transition ◽  
Tenascin C ◽  
Stage Renal Disease

Peritoneal deterioration causing structural changes and functional decline is a major complication of peritoneal dialysis (PD). The aim of this study was to explore effluent biomarkers reflecting peritoneal deterioration. In an animal study, rats were intraperitoneally administered with PD fluids adding 20 mM methylglyoxal (MGO) or 20 mM formaldehyde (FA) every day for 21 days. In the MGO-treated rats, tenascin-C (TN-C) levels in the peritoneal effluents were remarkably high and a cluster of TN-C-positive mesothelial cells with epithelial-to-mesenchymal transition- (EMT-) like change excessively proliferated at the peritoneal surface, but not in the FA-treated rats. Effluent matrix metalloproteinase-2 (MMP-2) levels increased in both the MGO- and FA-treated rats. In a clinical study at 18 centers between 2006 and 2013, effluent TN-C and MMP-2 levels were quantified in 182 PD patients with end-stage renal disease. Peritoneal function was estimated using the peritoneal equilibration test (PET). From the PET results, the D/P Cr ratio was correlated with effluent levels of TN-C (ρ= 0.57,p<0.001) and MMP-2 (ρ= 0.73,p<0.001). We suggest that TN-C in the effluents may be a diagnostic marker for peritoneal deterioration with EMT-like change in mesothelial cells in PD.

Ex Vivo Analysis of Dialysis Effluent-Derived Mesothelial Cells as an Approach to Unveiling the Mechanism of Peritoneal Membrane Failure

2006 ◽  
Vol 26 (1) ◽  
pp. 26-34 ◽  
Author(s):  
Manuel López-Cabrera ◽  
Abelardo Aguilera ◽  
Luiz S. Aroeira ◽  
Marta Ramírez-Huesca ◽  
M. Luisa Pérez-Lozano ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Ex Vivo ◽  
Functional Decline ◽  
Mesothelial Cells ◽  
Therapeutic Interventions ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Stromal Fibroblasts ◽  
Mesenchymal Transition ◽  
Ultrafiltration Failure

During peritoneal dialysis (PD), the peritoneum is exposed to bioincompatible dialysis fluids, which causes progressive fibrosis and angiogenesis and, ultimately, ultrafiltration failure. In addition, repeated episodes of peritonitis or hemoperitoneum may accelerate all these processes. Fibrosis has been classically considered the main cause of peritoneal membrane functional decline. However, in parallel with fibrosis, the peritoneum also displays increases in capillary number (angiogenesis) and vasculopathy in response to PD. Nowadays, there is emerging evidence pointing to peritoneal microvasculature as the main factor responsible for increased solute transport and ultrafiltration failure. However, the pathophysiologic mechanism(s) involved in starting and maintaining peritoneal fibrosis and angiogenesis remain(s) elusive. Peritoneal stromal fibroblasts have been considered (for many years) the cell type mainly involved in structural and functional alterations of the peritoneum; whereas mesothelial cells have been considered mere victims of peritoneal injury caused by PD. Recently, ex vivo cultures of effluent-derived mesothelial cells, in conjunction with immunohistochemical analysis of peritoneal biopsies from PD patients, have identified mesothelial cells as culprits, at least in part, in peritoneal membrane deterioration. This review discusses recent findings that suggest new peritoneal myofibroblastic cells may arise from local conversion of mesothelial cells by epithelial-to-mesenchymal transition during the repair responses that take place in PD. The transdifferentiated mesothelial cells may retain a permanent mesenchymal state, as long as initiating stimuli persist, and contribute to PD-induced fibrosis and angiogenesis, and hence to membrane failure. Future therapeutic interventions could be designated in order to prevent or reverse epithelial-to-mesenchymal transition of mesothelial cells, or its pernicious effects.

scholarly journals Effects of TGF-β1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells

2021 ◽  
Vol 22 (9) ◽  
pp. 4739
Author(s):  
Yunmee Lho ◽  
Jun-Young Do ◽  
Jung-Yoon Heo ◽  
A-Young Kim ◽  
Sang-Woon Kim ◽  
...  
Keyword(s):  
Mouse Model ◽  
Epithelial To Mesenchymal Transition ◽  
Mesothelial Cells ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Membrane Function ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Β Receptor ◽  
Receptor Inhibitor

We investigated the effectiveness of the transforming growth factor beta-1 (TGF-β) receptor inhibitor GW788388 on the epithelial to mesenchymal transition (EMT) using human peritoneal mesothelial cells (HPMCs) and examined the effectiveness of GW788388 on the peritoneal membrane using a peritoneal fibrosis mouse model. HPMCs were treated with TGF-β with or without GW788388. Animal experiments were conducted on male C57/BL6 mice. Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate. GW788388 was administered by once-daily oral gavage. The morphological change, cell migration, and invasion resulted from TGF-β treatment, but these changes were attenuated by cotreatment with GW788388. TGF-β-treated HPMCs decreased the level of the epithelial cell marker and increased the levels of the mesenchymal cell markers. Cotreatment with GW788388 reversed these changes. Phosphorylated Smad2 and Smad3 protein levels were stimulated with TGF-β and the change was attenuated by cotreatment with GW788388. For the peritoneal fibrosis mice, thickness and collagen deposition of parietal peritoneum was increased, but this change was attenuated by cotreatment with GW788388. GW788388, an orally available potent TGF-β receptor type 1 inhibitor, effectively attenuated TGF-β-induced EMT in HPMCs. Cotreatment with GW788388 improved peritoneal thickness and fibrosis, and recovered peritoneal membrane function in a peritoneal fibrosis mouse model.

scholarly journals Shorter daily dwelling time in peritoneal dialysis attenuates the epithelial-to-mesenchymal transition of mesothelial cells

2014 ◽  
Vol 15 (1) ◽  
Author(s):  
Yi-Che Lee ◽  
Yau-Sheng Tsai ◽  
Shih-Yuan Hung ◽  
Tsun-Mei Lin ◽  
Sheng-Hsiang Lin ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Epithelial To Mesenchymal Transition ◽  
Mesothelial Cells ◽  
Mesenchymal Transition ◽  
Dwelling Time

The John F. Maher Recipient Lecture 2004: Rage in the Peritoneum

2005 ◽  
Vol 25 (1) ◽  
pp. 8-11 ◽  
Author(s):  
An S. De Vriese
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Degradation Products ◽  
Mesothelial Cells ◽  
Cell Surface Receptor ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition

Several conditions in the peritoneal membrane of peritoneal dialysis (PD) patients promote the accumulation of advanced glycation end-products (AGEs), that is, the uremic state, exposure to high glucose concentrations, and exposure to glucose degradation products (GDPs). AGEs exert some of their biologic actions through binding with a cell surface receptor, termed RAGE. Interaction of AGEs with RAGE induces sustained cellular activation, including the production of the fibrogenic growth factor, transforming growth factor-beta (TGF-β). TGF-β is pivotal in the process of epithelial-to-mesenchymal transition, through which cells of epithelial origin acquire myofibroblastic characteristics. Myofibroblasts are involved in virtually all conditions of pathological fibrosis. Submesothelial fibrosis is an important feature in peritoneal biopsies of PD patients, especially of those with clinical problems. We therefore examined the role of RAGE in peritoneal fibrosis, in an animal model of uremia, of high glucose exposure, and of peritoneal dialysate exposure. All three models were characterized by accumulation of AGEs, upregulation of RAGE, and fibrosis. Antagonism of RAGE prevented the upregulation of TGF-β and fibrosis in the peritoneal membrane. We further examined the underlying mechanism of peritoneal fibrosis in the uremic model. Prominent myofibroblast transdifferentiation of mesothelial cells was identified by co-localization of cytokeratin and α-smooth muscle actin in submesothelial and interstitial fibrotic tissue. Antagonism of RAGE prevented conversion of mesothelial cells to myofibroblasts in uremia. In conclusion, we hypothesize that accumulation of AGEs in the peritoneal membrane, as a consequence of the uremic environment, chronic exposure to high glucose, and exposure to GDPs, results in an increased expression of RAGE. The interaction of AGEs with RAGE induces peritoneal fibrosis by virtue of upregulation of TGF-β and subsequent conversion of mesothelial cells into myofibroblasts.

Characterization of Epithelial-to-Mesenchymal Transition of Mesothelial Cells in a Mouse Model of Chronic Peritoneal Exposure to High Glucose Dialysate

2008 ◽  
Vol 28 (5_suppl) ◽  
pp. 29-33 ◽  
Author(s):  
Luiz S. Aroeira ◽  
Jesús Loureiro ◽  
Guadalupe T. González-Mateo ◽  
Vanessa Fernandez-Millara ◽  
Gloria del Peso ◽  
...  
Keyword(s):  
Mouse Model ◽  
High Glucose ◽  
Sequential Analysis ◽  
Epithelial To Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Mesothelial Cells ◽  
Dependent Manner ◽  
Peritoneal Membrane ◽  
Mesenchymal Transition ◽  
Peritoneal Dialysis Fluid

Animal models of peritoneal dialysis fluid (PDF) exposure are key tools in the study of mechanisms involved in alterations of the peritoneal membrane and in the design of therapies. We recently developed a mouse model of chronic peritoneal exposure to high glucose dialysate. Herein, we make a sequential analysis of the effects of glucose-based PDF on mouse peritoneal membrane and on mesothelium. We demonstrate that chronic exposure to PDF induces thickness and fibrosis of the peritoneal membrane in a time-dependent manner. We also show that mesothelial cells progressively detach and lose cytokeratin expression. In addition, we demonstrate that some mesothelial cells invade the submesothelial space, where they appear as cytokeratin- and alpha-smooth muscle actin-positive cells. These findings demonstrate that epithelial-to-mesenchymal transition (EMT) of mesothelial cells takes place in mouse peritoneum exposed to PDF, validating this model for the study of effects of drugs on the EMT process as a therapy for peritoneal deterioration.

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