Platelet derived growth factor B and epithelial mesenchymal transition of peritoneal mesothelial cells.
Platelet derived growth factor (PDGF) is involved in wound healing in various organ systems. Its potential role in the context of peritoneal injury following long-term peritoneal dialysis is unclear. We used an adenovirus expressing the B chain of PDGF (AdPDGF-B) to assess its effect on pro-fibrotic pathways in the peritoneal membrane. To assess the transforming growth factor (TGF) beta independent effects of PDGF, we over-expressed PDGF-B in the peritoneum of either wild-type mice (Smad3+/+) or those with a deletion of the TGFbeta signaling protein Smad3 (Smad3(-/-)). PDGF-B induced sustained angiogenesis in both Smad3+/+ and Smad3(-/-) mice. Despite increased collagen gene expression, collagen accumulation was transient and fibrogenesis was associated with induction of collagenase activity. We observed epithelial to mesenchymal transition (EMT) involving the peritoneal mesothelial cells, as shown by increased SNAIL and decreased E-Cadherin expression with evidence of mesothelial cells expressing both epithelial and mesenchymal markers. Unlike TGFbeta-induced EMT, PDGF-B exposure did not lead to mobilization of the mesothelial cells; they remained as a single monolayer throughout the observation period. This "non-invasive" EMT phenomenon is a novel finding and may have implications concerning the role of EMT in peritoneal fibrosis and injury to other organ systems. The observed effects were similar in Smad3(-/-) and Smad3+/+ animals, suggesting that the PDGF-B effects were independent of TGFbeta or Smad signaling.
Patel
Pranali
P
Department of Medicine, McMaster University, Division of Nephrology, St. Joseph's Hospital, 50 Charlton Ave E, Hamilton, Ontario, Canada L8P4A6.
West-Mays
Judy
J
Kolb
Martin
M
Rodrigues
Juan-Carlos
JC
Hoff
Catherine M
CM
Margetts
Peter J
PJ
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D004848:Epithelium / Q000502:physiology*; D005355:Fibrosis / Q000473:pathology; D018093:Gelatinases / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology; D010537:Peritoneum / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015820:Cadherins; D007527:Isoenzymes; D020574:Proto-Oncogene Proteins c-sis; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D018093:Gelatinases; D020782:Matrix Metalloproteinases