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 VEGF-165 impairs glomerular endothelial repair. We now studied the effects of systemic overexpression of hVEGF-165 during glomerular endothelial damage in this model. Hepatic gene transfer was performed by tail vein injection of a human VEGF-165 expression plasmid or LacZ control vector 24 hours prior to induction of anti-Thy1.1-nephritis. Rats receiving high dose VEGF-165 (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 VEGF-165 rats vs. LacZ rats. Proteinuria on day 6 was 142+/-29 mg/d (VEGF-165) 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 VEGF 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, VEGF-165 overexpression during early anti-Thy1.1 nephritis augmented glomerular injury, possibly mediated by systemic hypotension and/or uncoordinated endothelial repair. These findings raise important safety concerns in cases of systemic VEGF therapy and concomittant mesangiolytic injury.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2005

Author dc:creator

• Rong, Song

Contributors dc:contributor

• Flöge, Jürgen

• info:eu-repo/classification/ddc/610
• Medizin
• Vascular endothelial Growth Factor
• Mesangiale Immunglobulin-A-Glomerulonephritis
• Gentransfer
• Angiogenese
• VEGF
• mesangioproliferative nephritis
• gene transfer
• angiogenesis

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-123793%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:62211