Opposing roles for Smad2 and Smad3 in peritoneal fibrosis in vivo and in vitro

Am J Pathol. 2014 Aug;184(8):2275-84. doi: 10.1016/j.ajpath.2014.04.014. Epub 2014 Jun 10.

Abstract

Peritoneal fibrosis is a major cause of ultrafiltration failure in patients receiving continuous ambulatory peritoneal dialysis. Transforming growth factor (TGF)-β1 is an important mediator in this process; however, its signaling mechanisms had not been explored. Thus, we examined TGF-β1/Smad signaling in human peritoneal biopsy specimens associated with continuous ambulatory peritoneal dialysis. We found that TGF-β/Smad2/3 signaling was highly activated in patients with increased collagen deposition and thickening of the peritoneal membrane who were receiving continuous ambulatory peritoneal dialysis. Long-term exposure of wild-type mice to 4.25% peritoneal dialysis solution for 30 days induced significant peritoneal fibrosis with impaired peritoneal equilibrium, which was prevented in Smad3 knockout mice. In contrast, conditional Smad2 gene deletion in the peritoneum exacerbated peritoneal fibrosis and dysfunction. The contrasting roles of Smad2 and Smad3 in peritoneal fibrosis were also examined in vitro. Cultured mesothelial cells from Smad3 knockout mice were resistant to TGF-β1-induced collagen I production and the transition toward a myofibroblast phenotype as seen in wild-type cells, whereas Smad2 deficiency in mesothelial cells failed to modulate the profibrotic response to TGF-β1. In conclusion, this study found activation of TGF-β/Smad signaling in peritoneal fibrosis in patients receiving continuous ambulatory peritoneal dialysis and identifies opposing roles for Smad2 and Smad3 in peritoneal dialysis-associated peritoneal fibrosis. These findings provide a mechanistic basis for future therapies targeting TGF-β/Smad signaling in peritoneal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Female
  • Humans
  • Immunohistochemistry
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Peritoneal Dialysis, Continuous Ambulatory / adverse effects
  • Peritoneal Fibrosis / etiology
  • Peritoneal Fibrosis / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / physiology
  • Smad2 Protein / metabolism*
  • Smad3 Protein / metabolism*
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Smad2 Protein
  • Smad3 Protein
  • Transforming Growth Factor beta1