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.