Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells.
BACKGROUND
During continuous ambulatory peritoneal dialysis, the peritoneum is exposed to bioincompatible dialysis fluids that cause denudation of mesothelial cells and, ultimately, tissue fibrosis and failure of ultrafiltration. However, the mechanism of this process has yet to be elucidated.


METHODS
Mesothelial cells isolated from effluents in dialysis fluid from patients undergoing continuous ambulatory peritoneal dialysis were phenotypically characterized by flow cytometry, confocal immunofluorescence, Western blotting, and reverse-transcriptase polymerase chain reaction. These cells were compared with mesothelial cells from omentum and treated with various stimuli in vitro to mimic the transdifferentiation observed during continuous ambulatory peritoneal dialysis. Results were confirmed in vivo by immunohistochemical analysis performed on peritoneal-biopsy specimens.


RESULTS
Soon after dialysis is initiated, peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with a progressive loss of epithelial morphology and a decrease in the expression of cytokeratins and E-cadherin through an induction of the transcriptional repressor snail. Mesothelial cells also acquire a migratory phenotype with the up-regulation of expression of alpha2 integrin. In vitro analyses point to wound repair and profibrotic and inflammatory cytokines as factors that initiate mesothelial transdifferentiation. Immunohistochemical studies of peritoneal-biopsy specimens from patients undergoing continuous ambulatory peritoneal dialysis demonstrate the expression of the mesothelial markers intercellular adhesion molecule 1 and cytokeratins in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells.


CONCLUSIONS
Our results suggest that mesothelial cells have an active role in the structural and functional alteration of the peritoneum during peritoneal dialysis. The findings suggest potential targets for the design of new dialysis solutions and markers for the monitoring of patients.
Yáñez-Mó
María
M
Servicio de Inmunología, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Spain.
Lara-Pezzi
Enrique
E
Selgas
Rafael
R
Ramírez-Huesca
Marta
M
Domínguez-Jiménez
Carmen
C
Jiménez-Heffernan
José A
JA
Aguilera
Abelardo
A
Sánchez-Tomero
José A
JA
Bajo
M Auxiliadora
MA
Alvarez
Vincente
V
Castro
M Angeles
MA
del Peso
Gloria
G
Cirujeda
Antonio
A
Gamallo
Carlos
C
Sánchez-Madrid
Francisco
F
López-Cabrera
Manuel
M
D002465:Cell Movement; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D039001:Integrin alpha Chains / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D018715:Microscopy, Video; D009852:Omentum / Q000166:cytology; D010531:Peritoneal Dialysis, Continuous Ambulatory; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D004268:DNA-Binding Proteins; D039001:Integrin alpha Chains; D007375:Interleukin-1; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta