title: Role of endogenous vascular endothelial growth factor in tubular cell protection against acute cyclosporine toxicity.
abstract: 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.
authors.affiliation: FIS, Madrid, Spain.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Alvarez Arroyo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Susana
authors.initials: S
authors.lastname: Yagüe
authors.forename: Corina
authors.initials: C
authors.lastname: Lorz
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Jiménez
authors.forename: Carlos
authors.initials: C
authors.lastname: Soto
authors.forename: Antonio
authors.initials: A
authors.lastname: Barat
authors.forename: Emilia
authors.initials: E
authors.lastname: Belda
authors.forename: Francisco R
authors.initials: FR
authors.lastname: González-Pacheco
authors.forename: Juan J P
authors.initials: JJ
authors.lastname: Deudero
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Castilla
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Carlos
authors.initials: C
authors.lastname: Caramelo
mesh_terms: 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
chemical_list: 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