Abstract
Inhibiting vascular endothelial growth factor (VEGF) is a therapeutic option in diabetic microangiopathy. However, VEGF is needed at physiological concentrations to maintain glomerular integrity; complete VEGF blockade has deleterious effects on glomerular structure and function. Anti-VEGF therapy in diabetes raises the challenge of reducing VEGF-induced pathology without accelerating endothelial cell injury. Heparan sulfate (HS) act as a co-receptor for VEGF. Calcium dobesilate (CaD) is a small molecule with vasoprotective properties that has been used for the treatment of diabetic microangiopathy. Preliminary evidence suggests that CaD interferes with HS binding sites of fibroblast growth factor. We therefore tested the hypotheses that (1) CaD inhibits VEGF signaling in endothelial cells, (2) that this effect is mediated via interference between CaD and HS, and (3) that CaD ameliorates diabetic nephropathy in a streptozotocin-induced diabetic mouse model by VEGF inhibition. We found that CaD significantly inhibited VEGF165-induced endothelial cell migration, proliferation, and permeability. CaD significantly inhibited VEGF165-induced phosphorylation of VEGFR-2 and suppressed the activity of VEGFR-2 mediated signaling cascades. The effects of CaD in vitro were abrogated by heparin, suggesting the involvement of heparin-like domain in the interaction with CaD. In addition, VEGF121, an isoform which does not bind to heparin, was not inhibited by CaD. Using the proximity ligation approach, we detected inhibition of interaction in situ between HS and VEGF and between VEGF and VEGFR-2. Moreover, CaD reduced VEGF signaling in mice diabetic kidneys and ameliorated diabetic nephropathy and neuropathy, suggesting CaD as a VEGF inhibitor without the negative effects of complete VEGF blockade and therefore could be useful as a strategy in treating diabetic nephropathy.
Highlights
Diabetic nephropathy is one of the most important microvascular complications of diabetes mellitus and is responsible for 40–50% of all cases of end-stage renal disease (ESRD), despite various treatment strategies, such as intensive blood glucose control [1,2], lowering of blood pressure [3,4] or renin-angiotensin-system blockade [5] that have been established over the last 20 years [6,7]
We evaluated the inhibitory effect of Calcium dobesilate (CaD) on vascular endothelial growth factor (VEGF)-induced activation of the VEGFR-2 signaling pathway and the angiogenic response in human umbilical vein endothelial cells (HUVECs)
We showed that CaD significantly blocked VEGF and diabetes-induced VEGFR-2 phosphorylation, which is the main mediator of proliferation, migration, survival, and permeability in endothelial cells [47]
Summary
Diabetic nephropathy is one of the most important microvascular complications of diabetes mellitus and is responsible for 40–50% of all cases of end-stage renal disease (ESRD), despite various treatment strategies, such as intensive blood glucose control [1,2], lowering of blood pressure [3,4] or renin-angiotensin-system blockade [5] that have been established over the last 20 years [6,7]. VEGF has been observed to have an important role in maintaining the endothelial integrity because, anti-VEGF therapy in patients with solid tumours as well as conditional ablation of VEGF in adult mice led to microangiopathy [21,22]. These conflicting observations have led to the hypotheses that, under physiological conditions VEGF signaling is necessary to maintain endothelial stability, overexpressing VEGF and its signaling, as it is observed in diabetes, leads to endothelial damage and microvascular diseases
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