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.

• Authors: Hideki Yokoi, Masato Kasahara, Kiyoshi Mori, Yoshihisa Ogawa, Takashige Kuwabara, Hirotaka Imamaki, Tomoko Kawanishi, Kenichi Koga, Akira Ishii, Yukiko Kato, Keita P Mori, Naohiro Toda, Shoko Ohno, Hisako Muramatsu, Takashi Muramatsu, Akira Sugawara, Masashi Mukoyama, Kazuwa Nakao
• Journal: Kidney international (Kidney Int) Vol. 81 Issue 2 Pg. 160-9 (Jan 2012) ISSN: 1523-1755 [Electronic] United States
• PMID: 21881556 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD3 Complex
• Carrier Proteins
• Cytokines
• Dialysis Solutions
• Fibronectins
• Interleukin-1beta
• Ki-67 Antigen
• RNA, Messenger
• Transforming Growth Factor beta1
• Tumor Necrosis Factor-alpha
• pleiotrophin
• Connective Tissue Growth Factor
• chlorhexidine gluconate
• Chlorhexidine

Topics

• Adult
• Aged, 80 and over
• Animals
• Biopsy
• CD3 Complex
• Carrier Proteins (genetics, metabolism, pharmacology)
• Cell Movement (drug effects)
• Cells, Cultured
• Chlorhexidine (analogs & derivatives)
• Connective Tissue Growth Factor (genetics)
• Cytokines (genetics, metabolism, pharmacology)
• Dialysis Solutions (chemistry)
• Female
• Fibronectins (genetics)
• Gene Expression
• Humans
• Interleukin-1beta (metabolism)
• Ki-67 Antigen
• Lymphocyte Count
• Male
• Mice
• Middle Aged
• Mitotic Index
• Peritoneal Dialysis (adverse effects)
• Peritoneal Fibrosis (chemically induced, genetics, metabolism, physiopathology)
• Peritoneum (metabolism, pathology)
• Peritonitis (etiology, metabolism)
• Permeability
• RNA, Messenger (metabolism)
• T-Lymphocytes
• Transforming Growth Factor beta1 (genetics)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation