PloS one, 2020-01, Vol.15 (1), p.e0218494-e0218494
2020
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- Autor(en) / Beteiligte
- Titel
- Calcium dobesilate reduces VEGF signaling by interfering with heparan sulfate binding site and protects from vascular complications in diabetic mice
- Ist Teil von
- PloS one, 2020-01, Vol.15 (1), p.e0218494-e0218494
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2020
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0218494Titel-ID: cdi_plos_journals_2337982340
- Format
- –
- Schlagworte
- Animals, Anticoagulants, Aprotinin, Binding sites, Binding Sites - drug effects, Biology and Life Sciences, Calcium, Calcium Dobesilate - pharmacology, Calcium signalling, Cell injury, Cell migration, Cell Movement - drug effects, Complications, Complications and side effects, Diabetes, Diabetes mellitus, Diabetes Mellitus, Experimental - drug therapy, Diabetes Mellitus, Experimental - genetics, Diabetes Mellitus, Experimental - pathology, Diabetes therapy, Diabetic nephropathies, Diabetic Nephropathies - drug therapy, Diabetic Nephropathies - genetics, Diabetic Nephropathies - pathology, Diabetic nephropathy, Diabetic neuropathy, Diabetic retinopathy, Endothelial cells, Endothelial Cells - drug effects, Endothelial growth factors, Endothelium, Fibroblast growth factor, Fibroblast growth factors, Growth factors, Heparan sulfate, Heparin, Heparitin Sulfate - metabolism, Humans, Immunoglobulins, Inhibition, Injury prevention, Kidney diseases, Kidneys, Kinetics, Laboratory animals, Medical schools, Medicine and Health Sciences, Mice, Mice, Inbred NOD - genetics, Mice, Inbred NOD - growth & development, Nephrology, Nephropathy, Neuropathy, Ostomy, Permeability, Phosphorylation, Physiological effects, Physiology, Protection and preservation, Protein Binding - drug effects, Research and Analysis Methods, Signal Transduction - drug effects, Signaling, Software, Streptozocin, Structure-function relationships, Sulfates, Vascular endothelial growth factor, Vascular Endothelial Growth Factor A - antagonists & inhibitors, Vascular Endothelial Growth Factor A - genetics, Vascular Endothelial Growth Factor Receptor-2 - genetics, Vascular endothelial growth factor receptors