TGF-β1 promotes lymphangiogenesis during peritoneal fibrosis

Hiroshi Kinashi, Yasuhiko Ito, Masashi Mizuno, Yasuhiro Suzuki, Takeshi Terabayashi, Fumiko Nagura, Ryohei Hattori, Yoshihisa Matsukawa, Tomohiro Mizuno, Yukihiro Noda, Hayato Nishimura, Ryosuke Nishio, Shoichi Maruyama, Enyu Imai, Seiichi Matsuo, Yoshifumi Takei

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42 Citations (Scopus)

Abstract

Peritoneal fibrosis (PF) causes ultrafiltration failure (UFF) and is a complicating factor in long-term peritoneal dialysis. Lymphatic reabsorption also may contribute to UFF, but little is known about lymphangiogenesis in patients with UFF and peritonitis. We studied the role of the lymphangiogenesis mediator vascular endothelial growth factor-C (VEGF-C) in human dialysate effluents, peritoneal tissues, and peritoneal mesothelial cells (HPMCs). Dialysate VEGF-C concentration correlated positively with the dialysate-to-plasma ratio of creatinine (D/P Cr) and the dialysate TGF-b1 concentration. Peritoneal tissue from patients with UFF expressed higher levels of VEGF-C, lymphatic endothelial hyaluronan receptor-1 (LYVE-1), and podoplanin mRNA and contained more lymphatic vessels than tissue from patients without UFF. Furthermore, mesothelial cell and macrophage expression of VEGF-C increased in the peritoneal membranes of patients with UFF and peritonitis. In cultured mesothelial cells, TGF-b1 upregulated the expression of VEGF-C mRNA and protein, and this upregulation was suppressed by a TGF-b type I receptor (TGFbR-I) inhibitor. TGF-b1-induced upregulation of VEGF-C mRNAexpression in culturedHPMCs correlated with the D/P Cr of the patient from whom the HPMCs were derived (P, 0. 001). Moreover, treatment with a TGFbR-I inhibitor suppressed the enhanced lymphangiogenesis and VEGF-C expression associated with fibrosis in a rat model of PF. These results suggest that lymphangiogenesis associates with fibrosis through the TGF-b-VEGF-C pathway.

Original languageEnglish
Pages (from-to)1627-1642
Number of pages16
JournalJournal of the American Society of Nephrology
Volume24
Issue number10
DOIs
Publication statusPublished - 10-2013

All Science Journal Classification (ASJC) codes

  • Nephrology

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  • Cite this

    Kinashi, H., Ito, Y., Mizuno, M., Suzuki, Y., Terabayashi, T., Nagura, F., Hattori, R., Matsukawa, Y., Mizuno, T., Noda, Y., Nishimura, H., Nishio, R., Maruyama, S., Imai, E., Matsuo, S., & Takei, Y. (2013). TGF-β1 promotes lymphangiogenesis during peritoneal fibrosis. Journal of the American Society of Nephrology, 24(10), 1627-1642. https://doi.org/10.1681/ASN.2012030226