title: Suppression of cyclosporine a nephrotoxicity in vivo by transforming growth factor beta receptor-immunoglobulin G chimeric protein.
abstract: BACKGROUND
  Transforming growth factor (TGF)beta is implicated in the pathogenesis of cyclosporine A (CsA) nephrotoxicity. We examined the efficacy of TGF beta receptor (R)II/immunoglobulin (Ig)G Fc, a soluble chimeric protein consisting of the extracellular domain of human TGF beta RII and IgG1 Fc, on CsA nephrotoxicity in mice.
  
  
  METHODS
  Subcutaneous injection of CsA (25 mg/kg/d) was given daily to mice maintained on a low-sodium diet. On days 1 and 7, an expression vector carrying cDNA for either TGF beta RII/IgG Fc or beta-galactosidase was transfected into the skeletal muscles by electroporation. At 2 or 3 weeks of CsA administration, plasma and renal TGF beta 1 levels, and tubulointerstitial injury and fibrosis were evaluated.
  
  
  RESULTS
  After 2 weeks of CsA administration, plasma and renal TGF beta 1 levels increased to the maximum and then declined toward the baseline levels. Renal TGF beta 1 mRNA remained elevated until 3 weeks. Tubulointerstitial alterations became appreciable in 2 weeks and intensified by 3 weeks. At 2 weeks, the TGF beta RII/IgG Fc intervention abolished the increase in plasma TGF beta 1, attenuated the increase in renal TGF beta 1 by 50%, and markedly suppressed the histologic alterations. At 3 weeks, the histologic alterations remained markedly suppressed by the intervention, with no appreciable effects on the renal TGF beta 1 mRNA and protein.
  
  
  CONCLUSIONS
  The introduction of TGF beta RII/IgG Fc by gene transfer effectively abrogated CsA-induced tubulointerstitial alterations. Suppression of tubulointerstitial changes was evident at 3 weeks when renal TGF beta 1 mRNA and protein were comparable to those with CsA alone, indicating that early anti-TGF beta intervention is effective in suppressing the progression of CsA nephrotoxicity despite persistent increases in renal TGF beta 1 expression.
authors.affiliation: Department of Pediatrics, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Jing
authors.initials: J
authors.lastname: Xin
authors.forename: Toshio
authors.initials: T
authors.lastname: Homma
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
authors.forename: Enyu
authors.initials: E
authors.lastname: Imai
authors.forename: Iekuni
authors.initials: I
authors.lastname: Ichikawa
mesh_terms: D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D016572:Cyclosporine / Q000633:toxicity*; D005260:Female; D005355:Fibrosis; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000494:pharmacology; D007074:Immunoglobulin G / Q000235:genetics / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D018125:Receptors, Transforming Growth Factor beta / Q000097:blood / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
chemical_list: D024141:Collagen Type IV; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D016572:Cyclosporine