title: Transforming growth factor-β induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction.
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.
authors.affiliation: Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizuno
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kinashi
authors.forename: Akiho
authors.initials: A
authors.lastname: Sawai
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Noda
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Mizuno
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimizu
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Fujita
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Matsui
authors.forename: Shoichi
authors.initials: S
authors.lastname: Maruyama
authors.forename: Enyu
authors.initials: E
authors.lastname: Imai
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsuo
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Takei
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D042583:Lymphangiogenesis / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D000077293:Receptor, Transforming Growth Factor-beta Type I; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D011804:Quinolines; D000098853:Podoplanin
chemical_list: D008562:Membrane Glycoproteins; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011758:Pyrroles; D012333:RNA, Messenger; D000077293:Receptor, Transforming Growth Factor-beta Type I; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042582:Vascular Endothelial Growth Factor C; C506615:HTS 466284; D011804:Quinolines; C533408:Lyve1 protein, rat; C092025:Pdpn protein, rat; D000098853:Podoplanin; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; C467483:vascular endothelial growth factor C, mouse; C000625843:Tgfbr1 protein, rat