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Abstract: FR-PO416

Inhibition of Vascular Endothelial Growth Factor Receptor-2 Phosphorylation by Calcium Dobesilate Requires Interaction with Heparan Sulfate Binding Site

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Njau, Florence, Hannover Medical School, Hannover, Germany
  • Shushakova, Nelli, Nephrology and Hypertensiology, Hannover, Germany
  • Haller, Hermann G., Hannover Medical School, Hannover, Germany
Background

Inhibition of vascular endothelial growth factor (VEGF) is a therapeutic option in diabetic microangiopathy. However, VEGF is needed at physiological concentrations for the maintenance of glomerular integrity. Since VEGF exerts its effects on endothelial cells via binding to (1) the VEGF-receptor and (2) to heparan-sulfate (HS) as co-receptor partial blockade of VEGF may be a possible strategy. We tested the hypothesis that the small molecule calcium dobesilate (CaD) (1) inhibits VEGF signaling in endothelial cells, (2) that this effect is mediated via interference between CaD and heparan-sulfate (HS) binding sites and (3) CaD ameliorates diabetic nephropathy (DN) in a diabetic mouse model via inhibition of VEGF.

Methods

In vitro, the effect of CaD on VEGF signaling in endothelial cells (EC) together with the role of heparin was analyzed by Western blotting. EC function was assessed by migration, proliferation and permeability assays. Streptozotocin-treated mice (STZ) were treated with CaD and functional parameters as well as renal histology and inflammatory cells infiltration (immunohistochemistry) were measured at 6 and 12 weeks of hyperglycemia.

Results

CaD inhibited VEGF165-induced phosphorylation of VEGFR-2 kinase and suppressed the activity of VEGFR-2 mediated signaling cascades both in vitro and in diabetic animals. The effects of CaD in vitro were abrogated by exogenous heparin, suggesting the involvement of heparin-like domain in the interaction with CaD. VEGF121, which does not bind to heparin, was not inhibited by CaD. CaD restored tight junction protein expression and decreased VEGF-induced migration, proliferation and permeability in endothelial cells. CaD ameliorated glomerular pathology, reduced albuminuria and inflammatory cells infiltration in STZ-treated mice and reduced VEGF signaling in diabetic kidneys.

Conclusion

Our results suggest that CaD inhibits VEGFR-2 phosphorylation through the interaction between CaD and HS binding sites both in cultured endothelial cells and in vivo. CaD is a partial VEGF inhibitor without the negative effects of complete VEGF blockade and could be useful as therapeutic strategy in diabetic nephropathy.