Pleiotrophin triggers inflammation and increased peritoneal permeability leading to peritoneal fibrosis

Abstract

Long-term peritoneal dialysis induces peritoneal fibrosis with submesothelial fibrotic tissue. Although angiogenesis and inflammatory mediators are involved in peritoneal fibrosis, precise molecular mechanisms are undefined. To study this, we used microarray analysis and compared gene expression profiles of the peritoneum in control and chlorhexidine gluconate (CG)-induced peritoneal fibrosis mice. One of the 43 highly upregulated genes was pleiotrophin, a midkine family member, the expression of which was also upregulated by the solution used to treat mice by peritoneal dialysis. This growth factor was found in fibroblasts and mesothelial cells within the underlying submesothelial compact zones of mice, and in human peritoneal biopsy samples and peritoneal dialysate effluent. Recombinant pleiotrophin stimulated mitogenesis and migration of mouse mesothelial cells in culture. We found that in wild-type mice, CG treatment increased peritoneal permeability (measured by equilibration), increased mRNA expression of TGF-β1, connective tissue growth factor and fibronectin, TNF-α and IL-1β expression, and resulted in infiltration of CD3-positive T cells, and caused a high number of Ki-67-positive proliferating cells. All of these parameters were decreased in peritoneal tissues of CG-treated pleiotrophin-knockout mice. Thus, an upregulation of pleiotrophin appears to play a role in fibrosis and inflammation during peritoneal injury.

Pleiotrophin-induced endothelial cell migration is regulated by xanthine oxidase-mediated generation of reactive oxygen species

“…PTN is also involved in inflammatory pathologies (Pantazaka and Papadimitriou, 2012;Papadimitriou et al, 2009;Silver et al, 2012;Yokoi et al, 2012;Zhang et al, 2013) and activation of XO might be one of the mechanisms of its pro-inflammatory effects. In favor of this notion are data showing that interferon gamma (IFNγ), which is a known inducer of XO (Dupont et al, 1992), up-regulates PTN expression in capillaries of human atherosclerotic plaques through JAKs/STATs downstream effectors (Li et al, 2010).…”

“…Pleiotrophin (PTN) is a heparin binding growth factor with a significant regulatory role on inflammation, angiogenesis and cancer (Pantazaka and Papadimitriou, 2012;Papadimitriou et al, 2009;Silver et al, 2012;Yokoi et al, 2012;Zhang et al, 2013). In all cases, the best characterized PTN function is its effect on cell migration through its receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) (Lu et al, 2005;Polykratis et al, 2005) and integrin alpha v beta 3 (α ν β 3 ) .…”

Myofibroblastic Conversion and Regeneration of Mesothelial Cells in Peritoneal and Liver Fibrosis

“…22,29 Immunohistochemistry found that GFP þ MCs begin to express ACTA2 1 day after a single CG injection ( Figure 2C). After three CG injections, GFP þ cells were observed in the connective tissue, and the cells showed fibroblastic structure and expressed ACTA2 ( Figure 2C).…”

“…22,29 We examined whether 10 CG injections into the peritoneal cavity also causes injury to MCs in the liver as a visceral organ. With the use of the same Wt1…”

Peritonitis-induced peritoneal injury models for research in peritoneal dialysis review of infectious and non-infectious models

“…Lower doses of CG or shorter time courses produced milder and more infrequent development of peritoneal fibrosis [99,100]. Recent studies showed that a standard peritoneal fibrosis model could be produced in mice following treatment with 0.1% CG every other day or three times a week for 1-3 weeks [101][102][103][104][105][106][107][108].…”