Abstract: FR-PO355

Protective Effect of Vascular Endothelial Growth Factor-C on Renal Interstitial Fibrosis through Lymphangiogenesis in Mouse Unilateral Ureteral Obstruction

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Hasegawa, Shoko, Kyushu University, Higashi-ku, FUKUOKA, Japan
  • Nakano, Toshiaki, Kyushu University, Higashi-ku, FUKUOKA, Japan
  • Torisu, Kumiko, Kyushu University Hospital, Fukuoka, Japan
  • Tsuchimoto, Akihiro, Kyushu University, Higashi-ku, FUKUOKA, Japan
  • Eriguchi, Masahiro, Kyushu University, Higashi-ku, FUKUOKA, Japan
  • Masutani, Kosuke, Kyushu University, Higashi-ku, FUKUOKA, Japan
  • Tsuruya, Kazuhiko, None, Fukuoka, Japan
  • Kitazono, Takanari, Department of Medicine and Clinical Science, Fukuoka, Japan
Background

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 have previously reported the effect of vascular endothelial growth factor (VEGF)-C on lymphangiogenesis and fibrosis in the mouse kidney using the unilateral ureteral obstruction (UUO) model. At this time, we additionally investigated the effect of VEGF-C on inflammation and M1 and M2 macrophages. Furthermore, we investigated the effect of VEGF-C in vitro using lymphatic endothelial cells (LECs) by VEGF-C administration.

Methods

We continuously administered recombinant human VEGF-C to UUO model mice using an osmotic pump (UUO+VEGF-C group) for 14 days. We investigated the lymphangiogenesis (LYVE-1 staining, western blotting of VEGFR-3), inflammation (F4/80 staining, MCP-1 staining, ym-1 staining, western blotting of TGF-β1) and fibrosis (Sirius-red staining, western blotting of collagen 1). Additionally, we investigated the proliferation and adhesion molecules (ICAM-1, VCAM-1, E-selectin) of cultured LECs by administration of VEGF-C.

Results

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 (especially M1 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 LECs, administration of VEGF-C increased the proliferation of LECs and expression of adhesion molecules.

Conclusion

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.