Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

Abstract

Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A 165 b in diabetic nephropathy. Renal expression of VEGF-A 165 b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A 165 b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A 165 b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A 165 b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A 165 b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A 165 b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy.

Vascular endothelial growth factor-A165b prevents diabetic neuropathic pain and sensory neuronal degeneration

“…This twice weekly i.p. dosing regime has proven successful in the amelioration of diabetic nephropathy [21], traumatic nerve injury [16] and in vivo tumour models [22]. .…”

Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

“…12,[24][25][26] Importantly, postmitotic podocytes exhibit high levels of basal autophagy as a key regulator of podocyte and glomerular maintenance. 13 Additionally, a strong body of evidence supports the role for maintenance of endothelial function in diabetes to limit DN progression involving homeostasis of multiple systems 7,[27][28][29][30] such as NOS3/eNOS (nitric oxide synthase 3 [endothelial cell]) activity, 31 glycocalyx production, 32,33 EDN/endothelin actions [34][35][36][37][38] and balanced VEGF (vascular endothelial growth factor) 33,39,40 and ANGPT/angiopoietin systems. 41 Endothelial cells may also use autophagy as a coping mechanism to metabolic stress.…”

Bioinformatic analysis of specific genes in diabetic nephropathy

“…22 VEGFA isoform VEGF-A165b is proved to have the vasculoprotective effects against DN. 23 Besides, sub-network 2 with VEGFA as the centre node was screened in our paper. Function analysis showed that sub-network 2 was closely related with cell proliferation regulation related biological process.…”