VEGF(165) mediates glomerular endothelial repair

VEGF(165), the most abundant isoform in man, is an angiogenic cytokine that also regulates vascular permeability. Its function in the renal glomerulus , where it is expressed in visceral epithelial and mesangial cells, is unkn own. To assess the role of VEGF165 in glomerular disease, we administered a novel antagonist - a high-affinity, nuclease-resistant RNA aptamer coupled to 40-kDa polyethylene glycol(PEG) - to normal rats and to rats with mesan gioproliferative nephritis, passive Heymann nephritis (PHN), or puromycin a minonucleoside nephrosis (PAN). In normal rats, antagonism of VEGF(165) for 21 days failed to induce glomerular pathology or proteinuria. In rats with mesangioproliferative nephritis, the VEGF(165) aptamer (but not a sequence -scrambled control RNA or PEG alone) led to a reduction of glomerular endot helial regeneration and an increase in endothelial cell death, provoking an 8-fold increase in the frequency of glomerular microaneurysms by day 6. In contrast, early leukocyte influx and the proliferation, activation, and ma trix accumulation of mesangial cells were not affected in these rats. In ra ts with pi-IN or PAN, administration of the VEGF165 aptamer did not influen ce the course of proteinuria using various dosages and administration route s. These data identify VEGF(165) as a factor of central importance for endo thelial cell survival and repair in glomerular disease, and point to a pote ntially novel way to influence the course of glomerular diseases characteri zed by endothelial cell damage, such as various glomerulonephritides, throm botic microangiopathies, or renal transplant rejection.