Transforming growth factor-Β induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction

Yasuhiro Suzuki, Yasuhiko Ito, Masashi Mizuno, Hiroshi Kinashi, Akiho Sawai, Yukihiro Noda, Tomohiro Mizuno, Hideaki Shimizu, Yoshiro Fujita, Katsuyuki Matsui, Shoichi Maruyama, Enyu Imai, Seiichi Matsuo, Yoshifumi Takei

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)

Abstract

Inflammation is recognized as an important contributor to lymphangiogenesis; however, in tubulointerstitial lesions in human chronic kidney diseases, this process is better correlated with the presence of myofibroblasts rather than macrophages. As little is known about the interaction between lymphangiogenesis and renal fibrosis, we utilized the rat unilateral ureteral obstruction model to analyze inflammation, fibrosis, lymphangiogenesis, and growth factor expression. Additionally, we determined the relationship between vascular endothelial growth factor-C (VEGF-C), an inducer of lymphangiogenesis, and the profibrotic factor, transforming growth factor-Β1 (TGF-Β1). The expression of both TGF-Β1 and VEGF-C was detected in tubular epithelial and mononuclear cells, and gradually increased, peaking 14 days after ureteral obstruction. The kinetics and localization of VEGF-C were similar to those of TGF-Β1, and the expression of these growth factors and lymphangiogenesis were linked with the progression of fibrosis. VEGF-C expression was upregulated by TGF-Β1 in cultured proximal tubular epithelial cells, collecting duct cells, and macrophages. Both in vitro and in vivo, the induction of VEGF-C along with the overall appearance of lymphatics in vivo was specifically suppressed by the TGF-Β type I receptor inhibitor LY364947. Thus, TGF-Β1 induces VEGF-C expression, which leads to lymphangiogenesis.

Original languageEnglish
Pages (from-to)865-879
Number of pages15
JournalKidney International
Volume81
Issue number9
DOIs
Publication statusPublished - 01-05-2012

All Science Journal Classification (ASJC) codes

  • Nephrology

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