Vascular Endothelial Growth Factor165 Resolves Glomerular Inflammation and Accelerates Glomerular Capillary Repair in Rat Anti–Glomerular Basement Membrane Glomerulonephritis

Abstract

Abstract. Vascular endothelial growth factor (VEGF) is essential for maintenance of the glomerular capillary network. The present study investigated the effects of VEGF in rats with progressive crescentic glomerulonephritis (GN). Necrotizing and crescentic GN was induced in rats by injection of anti-rat glomerular basement membrane (GBM) antibody. The alterations of glomerular capillaries and glomerular VEGF expression were assessed. In addition, the effects of continuous VEGF 165 administration (10 g/100 g per d) on glomerular capillaries, glomerular inflammation, and the course of crescentic GN were examined. The appropriate timing of VEGF administration in progressive GN also was evaluated. In anti-GBM GN, necrotizing and crescentic glomerular lesions occurred by day 7, and newly formed necrotizing lesions reoccurred by week 3. Expression of VEGF was markedly reduced in necrotizing and crescentic lesions. Capillary repair was impaired after capillary destruction in necrotizing and crescentic glomeruli, which rapidly progressed to sclerotic glomeruli with chronic renal failure. In contrast, in the rats that received VEGF 165 administration from day 7, the necrotizing and crescentic lesions recovered and renal function significantly improved in week 4. This was evident by proliferating endothelial cells and glomerular capillary repair. In addition, VEGF administration decreased intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 expression in glomeruli (particularly on endothelial cells), reduced glomerular infiltrating CD8-postive and ED-1-positive cells, and inhibited the newly formed necrotizing lesions. VEGF administration was apparently effective against both the inflammatory and necrotizing glomerular lesions. These results suggest that VEGF administration resolves glomerular inflammation and accelerates glomerular recovery in the progressive necrotizing and crescentic GN. The therapeutic application of VEGF may be clinically useful for severe GN accompanied by extensive glomerular inflammation and endothelial injury.

Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease

“…This finding was surprising, because VEGF-A administration has been reported to be beneficial in several types of renal injury. 3,4,6,7 A potential explanation for this discrepancy is the timing of VEGF-A treatment and whether this maneuver occurs before or after onset of renal injury. The progression of renal injury is usually associated with a loss of capillaries, and so preventing capillary loss by VEGF-A might be beneficial.…”

“…[1][2][3][4][5] In these situations, administration of VEGF-A has been shown to improve renal histology and function. 3,4,6,7 In contrast, levels of both circulating and local VEGF-A are high in diabetes, and excessive VEGF-A has been shown to have a role in mediating glomerular hypertrophy, proteinuria, and retinopathy, 8,9 indicating that VEGF-A is deleterious in this unique situation. Given the fact that diabetic conditions are associated with a lower bioavailability of nitric oxide (NO), we have proposed a hypothesis that the deleterious effect of VEGF-A in diabetes could be attributed to a reduced bioavailability of endothelial NO in the kidney.…”

Sam68-Like Mammalian Protein 2, Identified by Digital Differential Display as Expressed by Podocytes, Is Induced in Proteinuria and Involved in Splice Site Selection of Vascular Endothelial Growth Factor

“…In contrast, podocyte-specific overexpression of VEGF 165 leads to a striking collapsing glomerulopathy (37). The systemic administration of VEGF 165 can accelerate glomerular repair in necrotizing glomerulonephritis (39). Differences between VEGF isoforms are potentially due to differences in binding to and release from the glomerular basement membrane (40,41).…”

The Continuing Story of Renal Repair with Stem Cells

“…We know from other experiments that the therapeutic effects of angiogenic growth factors such as vascular endothelial growth factor (VEGF) 7 and hepatocyte growth factor (HGF) 8 have been reported in tissue injury followed by fibrosis. VEGF and HGF are secreted by BMSC, and administration of VEGF or HGF improves hemodynamics, increases capillary density, accelerates tissue repair, and inhibits fibrosis in injured tissues.…”