title: TGF-β1 promotes lymphangiogenesis during peritoneal fibrosis.
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-β1 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-β1 upregulated the expression of VEGF-C mRNA and protein, and this upregulation was suppressed by a TGF-β type I receptor (TGFβR-I) inhibitor. TGF-β1-induced upregulation of VEGF-C mRNA expression in cultured HPMCs correlated with the D/P Cr of the patient from whom the HPMCs were derived (P<0.001). Moreover, treatment with a TGFβR-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-β-VEGF-C pathway.
authors.affiliation: Departments of Nephrology and Renal Replacement Therapy.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kinashi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizuno
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Terabayashi
authors.forename: Fumiko
authors.initials: F
authors.lastname: Nagura
authors.forename: Ryohei
authors.initials: R
authors.lastname: Hattori
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Matsukawa
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Mizuno
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Noda
authors.forename: Hayato
authors.initials: H
authors.lastname: Nishimura
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Nishio
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: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002460:Cell Line; D002710:Chlorhexidine / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D010530:Peritoneal Dialysis; D056627:Peritoneal Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D000098853:Podoplanin
chemical_list: D002710:Chlorhexidine; D018960:Hyaluronan Receptors; D008562:Membrane Glycoproteins; D053773:Transforming Growth Factor beta1; D042582:Vascular Endothelial Growth Factor C; C117468:PDPN protein, human; D000098853:Podoplanin; C010882:chlorhexidine gluconate