Role of endogenous vascular endothelial growth factor in tubular cell protection against acute cyclosporine toxicity.
BACKGROUND
Recent studies have shown that exogenous administration of vascular endothelial growth factor (VEGF) is protective against cyclosporine A (CsA) renal toxicity. No data are available, however, on the possible role of endogenous VEGF. Our objective was to examine whether endogenous VEGF has a significant role in the renal response against CsA toxicity.


METHODS
In vivo, we used high-dose (50-150 mg/kg/day) CsA +/- specific goat anti-mouse VEGF blocking monoclonal antibody (alpha-VEGF) in mice. In vitro, we exposed mouse tubular cells (MCT) to CsA +/- alpha-VEGF.


RESULTS
alpha-VEGF markedly enhanced CsA renal toxicity, inducing severe tubular damage and increased blood urea nitrogen. In animals treated with CsA + alpha-VEGF, damage progressed to generalized tubular injury (histology) and apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling) with associated anemia and reticulocytosis (18 days of treatment). CsA + alpha-VEGF treatments strikingly increased tubular VEGF and Bcl-xL proteins. In vitro, autocrine production of VEGF by MCT was identified by Western blot. Of specific interest, CsA toxicity in MCT increased significantly in the presence of alpha-VEGF.


CONCLUSIONS
Endogenous VEGF has a relevant role in the renal tubular defense against CsA toxicity. Blockade of the VEGF effect by alpha-VEGF results in clear-cut intensification of the tubular injury and appearance of regenerative anemia in the CsA + alpha-VEGF-treated animals. The occurrence of both in vivo and in vitro effects of VEGF blockade provides evidence of a direct protective effect of VEGF on the tubular cell.
Alvarez Arroyo
María Victoria
MV
FIS, Madrid, Spain.
Suzuki
Yusuke
Y
Yagüe
Susana
S
Lorz
Corina
C
Jiménez
Sonsoles
S
Soto
Carlos
C
Barat
Antonio
A
Belda
Emilia
E
González-Pacheco
Francisco R
FR
Deudero
Juan J P
JJ
Castilla
María Angeles
MA
Egido
Jesús
J
Ortiz
Alberto
A
Caramelo
Carlos
C
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D016572:Cyclosporine / Q000506:poisoning*; D019610:Cytoprotection / Q000502:physiology*; D004357:Drug Synergism; D016228:Endothelial Growth Factors / Q000276:immunology / Q000502:physiology*; D005260:Female; D007166:Immunosuppressive Agents / Q000506:poisoning*; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000502:physiology*; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D008222:Lymphokines / Q000276:immunology / Q000502:physiology*; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051020:bcl-X Protein
D000911:Antibodies, Monoclonal; C494812:Bcl2l1 protein, mouse; D016228:Endothelial Growth Factors; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D019253:Proto-Oncogene Proteins c-bcl-2; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051020:bcl-X Protein; D016572:Cyclosporine