title: Nitric oxide modulates vascular endothelial growth factor and receptors in chronic cyclosporine nephrotoxicity.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) is involved in angiogenesis, wound healing, and inflammation and exerts its effect via tyrosine kinase receptors, fms-like tyrosine kinase (Flt-1) and fetal liver kinase (Flk-1 or KDR). We have previously shown that VEGF is up-regulated in a model of chronic cyclosporine (CsA) nephrotoxicity and that l-arginine (l-Arg) improved while N-nitro-l-arginine-methyl ester (L-NAME) worsened fibrosis. We examined the role of nitric oxide modulation on VEGF in this model.
  
  
  METHODS
  Pair-fed salt-depleted rats were administered CsA, CsA + L-NAME, CsA +l-Arg, vehicle (VH), VH + L-NAME or VH +l-Arg and were sacrificed at 7 or 28 days. Physiologic and histologic changes were studied in addition to the mRNA expression of VEGF and its receptors Flt-1 and KDR/Flk-1 by Northern blot and the protein expression of VEGF by Western blot and immunohistochemical staining.
  
  
  RESULTS
  While L-NAME worsened renal function and histology, l-Arg had the opposite beneficial effect in CsA-treated rats. VEGF mRNA and protein expressions increased with CsA, further increased with L-NAME and became significantly reduced with L-Arg. Flt-1 expression was similar in all groups. On the other hand, KDR/Flk-1 mRNA expression was modulated in a fashion similar to VEGF. Also, nitric oxide modulation did not have an effect on VH-treated rats.
  
  
  CONCLUSIONS
  VEGF expression in chronic CsA nephrotoxicity is increased by nitric oxide blockade and decreased by nitric oxide enhancement. Moreover, VEGF probably exerted its effect via the KDR/Flk-1 receptor. The actions of VEGF in this model remain speculative, but it is probable that VEGF plays a role, either independently or through nitric oxide, in CsA-induced fibrosis.
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA. Fuad.Shihab@hsc.utah.edu
authors.forename: Fuad S
authors.initials: FS
authors.lastname: Shihab
authors.forename: William M
authors.initials: WM
authors.lastname: Bennett
authors.forename: Jorge
authors.initials: J
authors.lastname: Isaac
authors.forename: Hong
authors.initials: H
authors.lastname: Yi
authors.forename: Takeshi F
authors.initials: TF
authors.lastname: Andoh
mesh_terms: D000818:Animals; D002908:Chronic Disease; D016572:Cyclosporine / Q000506:poisoning*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D016572:Cyclosporine; C501164:Flt1 protein, rat; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D019331:NG-Nitroarginine Methyl Ester