Vascular endothelial growth factor-C ameliorates renal interstitial fibrosis through lymphangiogenesis in mouse unilateral ureteral obstruction

Shoko Hasegawa, Toshiaki Nakano, Kumiko Torisu, Akihiro Tsuchimoto, Masahiro Eriguchi, Naoki Haruyama, Kosuke Masutani, Kazuhiko Tsuruya, Takanari Kitazono

Research output: Contribution to journalArticle

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Abstract

Renal fibrosis is the final common pathway of chronic kidney diseases. Lymphatic vessel (LV) proliferation is found in human renal diseases and other fibrotic diseases, suggesting that lymphangiogenesis is associated with the progression or suppression of kidney diseases. However, the purpose of LV proliferation is not completely understood. We investigated the effect of vascular endothelial growth factor (VEGF)-C on lymphangiogenesis, inflammation, and fibrosis in the mouse kidney using the unilateral ureteral obstruction (UUO) model. In UUO mice, significant proliferation of LVs was accompanied by tubulointerstitial nephritis and fibrosis. We continuously administered recombinant human VEGF-C to UUO model mice using an osmotic pump (UUO+VEGF-C group). Lymphangiogenesis was significantly induced in the UUO+VEGF-C group compared with the vehicle group, despite similar numbers of capillaries in both groups. The number of infiltrating macrophages, and levels of inflammatory cytokines and transforming growth factor-β1 were reduced in the UUO+VEGF-C group compared with the vehicle group. Renal fibrosis was consequently attenuated in the UUO+VEGF-C group. In cultured lymphatic endothelial cells, administration of VEGF-C increased the activity and proliferation of lymphatic endothelial cells (LECs) and expression of adhesion molecules such as vascular cell adhesion molecule-1. These findings suggest that induction of lymphangiogenesis ameliorates inflammation and fibrosis in the renal interstitium. Enhancement of the VEGF-C signaling pathway in LECs may be a therapeutic strategy for renal fibrosis.

Original languageEnglish
Pages (from-to)1439-1452
Number of pages14
JournalLaboratory Investigation
Volume97
Issue number12
DOIs
Publication statusPublished - Dec 1 2017

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Lymphangiogenesis
Vascular Endothelial Growth Factor C
Ureteral Obstruction
Fibrosis
Kidney
Lymphatic Vessels
Endothelial Cells
Inflammation
Interstitial Nephritis
Vascular Cell Adhesion Molecule-1
Kidney Diseases
Cell Adhesion Molecules
Transforming Growth Factors
Chronic Renal Insufficiency
Macrophages
Cytokines

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Vascular endothelial growth factor-C ameliorates renal interstitial fibrosis through lymphangiogenesis in mouse unilateral ureteral obstruction. / Hasegawa, Shoko; Nakano, Toshiaki; Torisu, Kumiko; Tsuchimoto, Akihiro; Eriguchi, Masahiro; Haruyama, Naoki; Masutani, Kosuke; Tsuruya, Kazuhiko; Kitazono, Takanari.

In: Laboratory Investigation, Vol. 97, No. 12, 01.12.2017, p. 1439-1452.

Research output: Contribution to journalArticle

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