title: Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury.
abstract: Appropriate fluid balance is important for good clinical outcomes and survival in patients on peritoneal dialysis. We recently reported that lymphangiogenesis associated with fibrosis developed in the peritoneal cavity via the transforming growth factor-β1-vascular endothelial growth factor-C (VEGF-C) pathway. We investigated whether VEGF receptor-3 (VEGFR-3), the receptor for VEGF-C and -D, might be a new target to improve net ultrafiltration by using adenovirus-expressing soluble VEGFR-3 (Adeno-sVEGFR-3) in rodent models of peritoneal injury induced by methylglyoxal (MGO). We demonstrated that lymphangiogenesis developed in these MGO models, especially in the diaphragm, indicating that lymphangiogenesis is a common feature in the peritoneal cavity with inflammation and fibrosis. In MGO models, VEGF-D was significantly increased in the diaphragm; however, VEGF-C was not significantly upregulated. Adeno-sVEGFR-3, which was detected on day 50 after administration via tail vein injections, successfully suppressed lymphangiogenesis in the diaphragm and parietal peritoneum in mouse MGO models without significant effects on fibrosis, inflammation, or neoangiogenesis. Drained volume in the peritoneal equilibration test using a 7.5% icodextrin peritoneal dialysis solution (the 7.5% icodextrin peritoneal equilibration test) was improved by Adeno-sVEGFR-3 on day 22 (P<0.05) and day 50 after reduction of inflammation (P<0.01), indicating that the 7.5% icodextrin peritoneal equilibration test identifies changes in lymphangiogenesis. The solute transport rate was not affected by suppression of lymphangiogenesis. In human peritoneal dialysis patients, the dialysate to plasma ratio of creatinine positively correlated with the dialysate VEGF-D concentration (P<0.001). VEGF-D mRNA was significantly higher in the peritoneal membranes of patients with ultrafiltration failure, indicating that VEGF-D is involved in the development of lymphangiogenesis in peritoneal dialysis patients. These results indicate that VEGFR-3 is a new target to improve net ultrafiltration by suppressing lymphatic absorption and that the 7.5% icodextrin peritoneal equilibration test is useful for estimation of lymphatic absorption.
authors.affiliation: Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Terabayashi
authors.affiliation: Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizuno
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.affiliation: Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kinashi
authors.affiliation: Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sakata
authors.affiliation: Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Iguchi
authors.affiliation: Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Tawada
authors.affiliation: Department of Emergency Medicine, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Nishio
authors.affiliation: Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Maruyama
authors.affiliation: Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Nakayamadera Imai Clinic, Takarazuka, Japan.
authors.forename: Enyu
authors.initials: E
authors.lastname: Imai
authors.affiliation: Department of Nephrology and Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsuo
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Takei
mesh_terms: D000818:Animals; D003404:Creatinine / Q000032:analysis / Q000097:blood; D015314:Dialysis Solutions / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005936:Glucans; D005947:Glucose; D006801:Humans; D000077607:Icodextrin; D007150:Immunohistochemistry; D042583:Lymphangiogenesis / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010530:Peritoneal Dialysis / Q000009:adverse effects* / Q000379:methods; D010537:Peritoneum / Q000187:drug effects* / Q000293:injuries; D011765:Pyruvaldehyde / Q000009:adverse effects*; D018709:Statistics, Nonparametric; D014462:Ultrafiltration / Q000379:methods*; D042643:Vascular Endothelial Growth Factor D / Q000032:analysis / Q000097:blood; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D015314:Dialysis Solutions; D005936:Glucans; D042643:Vascular Endothelial Growth Factor D; D000077607:Icodextrin; D011765:Pyruvaldehyde; D003404:Creatinine; D040321:Vascular Endothelial Growth Factor Receptor-3; D005947:Glucose