Calcium dobesilate may alleviate diabetes-induced endothelial dysfunction and inflammation

Abstract

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. However, the pathogenesis of DKD remains unclear, and no effective treatments for the disease are available. Thus, there is an urgent need to elucidate the pathogenic mechanisms of DKD and to develop more effective therapies for this disease. Human umbilical vein endothelial cells (HUVECs) were cultured using different D-glucose concentrations to determine the effect of high glucose (HG) on the cells. Alternatively, HUVECs were incubated with 100 µmol/l calcium dobesilate (CaD) to detect its effects. The authors subsequently measured HUVEC proliferation via cell counting kit-8 assays. In addition, HUVEC angiogenesis was investigated via migration assays and fluorescein isothiocyanate (FITC)-labelled bovine serum albumin (BSA) permeability assays. The content or distribution of markers of endothelial dysfunction [vascular endothelial growth factor (VEGF), VEGF receptor (R) and endocan) or inflammation [intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1 and pentraxin-related protein (PTX3)] was evaluated via reverse transcription-quantitative polymerase chain reaction and western blotting. HG treatment induced increased in VEGF, VEGFR, endocan, ICAM-1, MCP-1 and PTX3 mRNA and protein expression in HUVECs. HG treatment for 24 to 48 h increased cell proliferation in a time-dependent manner, but the cell proliferation rate was decreased at 72 h of HG treatment. Conversely, CaD inhibited abnormal cell proliferation. HG treatment also significantly enhanced HVUEC migration compared to the control treatment. In contrast, CaD treatment partially inhibited HUVEC migration compared to HG exposure. HG-treated HUVECs exhibited increased FITC-BSA permeability compared to control cells cultured in medium alone; however, CaD application prevented the HG-induced increase in FITC-BSA permeability and suppressed HG-induced overexpression of endothelial markers (VEGF, VEGFR-2, endocan) and inflammation markers (ICAM-1, MCP-1, PTX3) in HUVECs. CaD has angioprotective properties and protects endothelial cells partly by ameliorating HG-induced inflammation. The current results demonstrated the potential applicability of CaD to the treatment of diabetic nephropathy, particularly during the early stages of this disease.

Calcium dobesilate reduces VEGF signaling by interfering with heparan sulfate binding site and protects from vascular complications in diabetic mice

“…Consistent with the anti-migratory function, CaD also abolished VEGF-induced polymerization of actin in lamellipodia-like structures. Zhou and colleagues have recently demonstrated an inhibition of endothelial cell proliferation and migration by CaD under hyperglycemic conditions [25], which they attributed to the corresponding changes in VEGF expression. Instead, and heparin (10 μg/ml) were pre-mixed and incubated at 37˚C for 60 min prior to HUVECs stimulation for 2 min.…”

“…At present, CaD is approved in numerous countries for the treatment of diabetic retinopathy another important complication of diabetes mellitus and its efficacy has been analyzed in a recent meta-analysis [23,24]. Moreover, recent studies have demonstrated that CaD can be safely and effectively used to treat diabetic nephropathy in type 2 diabetic patients [25,26]. However, the pharmacology of CaD is poorly understood.…”

Calcium dobesilate reduces VEGF signaling by interfering with heparan sulfate binding site and protects from vascular complications in diabetic mice

“…In addition, our experiments show that CaD prevents the increase and upregulation/activation of several pro-inflammatory cytokines (IL-6, CXCL1, IL-1ß, TNF-α, and MCP-1) that play a significant role in renal-disease progression. Although the anti-inflammatory properties of CaD have been previously reported (42,46), to the best of our knowledge, our report is the first involving a diabetic-nephropathy animal model. These findings are therefore important due to the pivotal role of inflammation in the pathogenesis of diabetic nephropathy.…”

“…Consistent with the anti-migratory function, CaD also abolished VEGF-induced polymerization of actin in lamellipodia-like structures. Zhou and colleagues have recently demonstrated an inhibition of endothelial cell proliferation and migration by CaD under hyperglycemic conditions (42), which they attributed to the corresponding changes in VEGF expression. Instead, we demonstrate a direct effect of CaD on VEGF signaling.…”

“…CaD inhibited VEGF-induced endothelial permeability and could protect against blood-brain-barrier leakage. Such an effect was observed in the retina correlated with a decrease in the levels of VEGF in the retina (47), however, was explained by a direct effect of CaD on VEGF expression (42). Although we also observed down-regulation of VEGF production in the kidneys from STZ mice, we believe that this is a secondary phenomenon after improvement of endothelial cell function.…”