Kidney Week

Abstract: SA-PO936

Connective Tissue Growth Factor Is Correlated with Peritoneal Lymphangiogenesis

Session Information

• Dialysis: Peritoneal Dialysis - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Dialysis

• 703 Dialysis: Peritoneal Dialysis

Authors

• Kinashi, Hiroshi, Aichi Medical University, Nagakute, Japan

Hiroshi Kinashi,

• Toda, Naohiro, Kansai Electric Power Hospital, Osaka, OSAKA-FU, Japan

Naohiro Toda,

• Nguyen, Tri Q., University Medical Center Utrecht, Utrecht, Netherlands

Tri Q. Nguyen,

• Suzuki, Yasuhiro, Nagoya University Graduate School of Medicine, Nagoya, Japan

Yasuhiro Suzuki,

• Katsuno, Takayuki, Aichi Medical University, Nagakute, Japan

Takayuki Katsuno,

• Yokoi, Hideki, Kyoto University Graduate School of Medicine, Kyoto City, Japan

Hideki Yokoi,

• Aten, Jan, Academic Medical Center, Amsterdam, Netherlands

Jan Aten,

• Mizuno, Masashi, Nagoya University Graduate School of Medicine, Nagoya, Japan

Masashi Mizuno,

• Maruyama, Shoichi, Nagoya University Graduate School of Medicine, Nagoya, Japan

Shoichi Maruyama,

• Yanagita, Motoko, Kyoto University Graduate School of Medicine, Kyoto City, Japan

Motoko Yanagita,

• Goldschmeding, Roel, University Medical Center Utrecht, Utrecht, Netherlands

Roel Goldschmeding,

• Ito, Yasuhiko, Aichi Medical University, Nagakute, Japan

Yasuhiko Ito,

Background

Lymphatic absorption in peritoneal cavity may contribute to ultrafiltration failure in peritoneal dialysis (PD). Lymphatic vessels develop during PD-related peritoneal fibrosis. Connective tissue growth factor (CTGF, also known as CCN2) is an important determinant of fibrotic tissue remodeling, but little is known about its possible involvement in lymphangiogenesis. We studied the relationship between CTGF and lymphangiogenesis in association with PD.

Methods

Protein levels of CTGF and vascular endothelial growth factor-C (VEGF-C), a major lymphangiogenic factor, were measured in 77 human PD effluents. Messenger RNA (mRNA) expression of CTGF, lymphatic markers (lymphatic endothelial hyaluronan receptor-1 [LYVE-1] and podoplanin), and VEGF-C was analyzed in 56 human peritoneal biopsies. CTGF and VEGF-C mRNA were assessed in cultured human peritoneal mesothelial cells (HPMC) (N=21) treated with transforming growth factor-β1 (TGF-β1). CTGF involvement in diaphragamatic lymphangiogenesis was explored in a rat peritoneal fibrosis model induced by chlorhexidine gluconate (CG). Finally, the role of CTGF inhibition in peritoneal lymphangiogenesis was evaluated in the CG model using CTGF knockout mice.

Results

A positive correlation was observed between CTGF and VEGF-C concentration in human PD effluents (R=0.428, p<0.001). CTGF mRNA positively correlated with VEGF-C (R=0.67, p<0.001), LYVE-1 (R=0.638, p<0.001), and podoplanin (R=0.592, p<0.001) mRNA in human peritoneal biopsies. There was a positive relationship between CTGF and VEGF-C mRNA fold-increase in HPMC at 12 hours after TGF-β1 treatment (R=0.722, p<0.001). Immunohistochemstry and in situ hybridization showed that CTGF, VEGF-C, and LYVE-1-positive lymphatic vessels were increased in the rat diaphragm of CG model compared with controls. CTGF expression positively correlated with VEGF-C expression (p<0.001) and lymphatics (p<0.05) in the rat diaphragm of CG model. Finally, CTGF gene deletion significantly reduced VEGF-C expression and suppressed lymphangiogenesis in the mouse peritoneum of CG model.

Conclusion

Our results suggest a close relationship between CTGF and PD-associated lymphangiogenesis.