Vascular endothelial growth factor (VEGF(121)) protects rats from renal infarction in thrombotic microangiopathy

Background. Renal thrombotic microangiopathy, typified by the hemolytic ure mic syndrome, is associated with endothelial cell injury in which the prese nce of cortical necrosis, extensive glomerular involvement, and arterial oc clusive lesions correlates with a poor clinical outcome. We hypothesized th at the endothelial survival factor vascular endothelial growth factor (VEGF ) may provide protection. Method. Severe, necrotizing, thrombotic microangiopathy was induced in rats by the renal artery perfusion of antiglomerular endothelial antibody, foll owed by the administration of VEGF or vehicle, and renal injury was evaluat ed. Results. Control rats developed severe glomerular and tubulointerstitial in jury with extensive renal necrosis. The administration of VEGF significantl y reduced the necrosis, preserved the glomerular endothelium and arterioles , and reduced the number of apoptotic cells in glomeruli (at 4 hours) and i n the tubulointerstitium (at 4 days). The prosurvival effect of VEGF for en dothelium may relate in part to the ability of VEGF to protect endothelial cells from factor-induced apoptosis, as demonstrated for tumor necrosis fac tor-alpha (TNF-alpha.), which was shown to be up-regulated through the cour se of this model of renal microangiopathy. Endothelial nitric oxide synthas e expression was preserved in VEGF-treated rats compared with its marked de crease in the surviving glomeruli and interstitium of the antibody-treated rats that did not receive VEGF. Conclusions. VEGF protects against renal necrosis in this model of thrombot ic microangiopathy. This protection may be mediated by maintaining endothel ial nitric oxide production and/or preventing endothelial cell death.