title: Hyaluronan-induced VEGF-C promotes fibrosis-induced lymphangiogenesis via Toll-like receptor 4-dependent signal pathway.
abstract: Hyaluronan (HA), a component of the extracellular matrix, modulates cellular behavior including angiogenesis. However, little is known about the effect of HA on lymphangiogenesis in fibrosis model. In this study, we investigated the roles of HA in lymphangiogenesis of unilateral ureteral obstruction (UUO). We found that HA cooperated synergistically with vascular endothelial cell growth factor-C to stimulate capillary-like tube formation and increase migration of cells in a haptotaxis assay. Accumulation of HA in the cortical interstitial space was positively correlated with the number of lymphatic vessels after UUO. Depletion of macrophages with clodronate decreased UUO-induced HA accumulation and lymphangiogenesis. Additionally, hyaluronan synthase (HAS) mRNA expression and HA production were increased in bone marrow-derived macrophages upon stimulation with TGF-β1. Transfer of mHAS2 and mHAS3 knock-down CD11b-positive macrophages to SCID mice resulted in a partial decrease in UUO-induced lymphangiogenesis. HA increased expression of vascular endothelial cell growth factor-C in macrophages. Vascular endothelial cell growth factor-C expression and LYVE-1-positive lymphatic area was significantly lower in the UUO-kidney from TLR4 null mice than that from TLR4 wild-type mice. Collectively, these results suggest that HA increases lymphangiogenesis in renal fibrosis model and also stimulates vascular endothelial cell growth factor-C production from macrophages through Toll-like receptor 4-dependent signal pathway.
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea; Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Republic of Korea.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Jung
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea; Korea Food Research Institute, Seongnam, Republic of Korea.
authors.forename: Ae Sin
authors.initials: AS
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Tung
authors.initials: T
authors.lastname: Nguyen-Thanh
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea; Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Republic of Korea.
authors.forename: Kyung Pyo
authors.initials: KP
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea; Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Republic of Korea.
authors.forename: Sik
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pathology, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.affiliation: Department of Urology, Chonbuk National University Medical School, Jeonju, Republic of Korea; Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Republic of Korea.
authors.forename: Myung Ki
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Department of Physiology, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea; Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Republic of Korea. Electronic address: parksk@jbnu.ac.kr.
authors.forename: Sung Kwang
authors.initials: SK
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea; Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Republic of Korea. Electronic address: kwon@jbnu.ac.kr.
authors.forename: Won
authors.initials: W
authors.lastname: Kim
mesh_terms: D000818:Animals; D004002:Clodronic Acid / Q000737:chemistry; D005355:Fibrosis; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008081:Liposomes / Q000737:chemistry; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
chemical_list: D004002:Clodronic Acid; D006023:Glycoproteins; D006820:Hyaluronic Acid; D008081:Liposomes; D026901:Membrane Transport Proteins; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; D042582:Vascular Endothelial Growth Factor C; C493487:Tlr4 protein, mouse; C492273:LYVE1 protein, mouse
keywords: Hyaluronan; Kidney fibrosis; Lymphangiogenesis; Lymphatic endothelial cells; Macrophages; Toll-like receptor 4