Systemic overexpression of hVEGF-165 in rat liver impairs glomerular healing in experimental mesangioproliferative nephritis

Vascular endothelial growth factor (VEGF) regulates vascular permeability and endothelial cell proliferation. In the rat anti-Thy1.1 mesangioproliferative nephritis inhibition of VEGF165 impairs glomerular endothelial repair. We now studied the effects of systemic overexpression of VEGF165 during glomerular endothelial damage in this model. Hepatic gene transfer was performed by tail vein injection of a human VEGF165 expression plasmid or LacZ control vector 24 hours prior to induction of anti-Thy1.1-nephritis. Rats receiving high dose VEGF165 (800 μg plasmid; serum levels at 48h 762 434 pg/ml vs. <30 pg/ml in LacZ rats) showed generalized edema and transient hypotension on days 0 and 1, whereas LacZ treated animals remained normotensive. On days 2 and/or 6 after disease induction, mesangiolysis, glomerular cell proliferation and glomerular monocyte/macrophage infiltration was significantly increased in high dose VEGF165 rats vs. LacZ rats. Proteinuria on day 6 was 142 ± 29 mg/d (VEGF165) vs. 66 ± 41 mg/d (LacZ). Aggravation of glomerular injury was not due to altered anti-Thy1.1 antibody binding after VEGF165 gene transfer. Rather, a dihydralazine treated control group with sham gene transfer showed that systemic hypotension per se augmented glomerular injury. However, hepatic overexpression of 8-fold lower VEGF165 doses in anti-Thy1.1-nephritis also resulted in augmented damage on day 2 and failed to improve glomerular histology on day 6. In summary, contrary to our expectation, VEGF165 overexpression during early anti-Thy1.1 nephritis augmented glomerular injury,