Suppression of Cyclosporine a Nephrotoxicity in Vivo by Transforming Growth Factor Beta Receptor-Immunoglobulin G Chimeric Protein

Transplantation. 2004 May 15;77(9):1433-42. doi: 10.1097/01.tp.0000121502.60664.ab.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Collagen Type IV / metabolism
  • Cyclosporine / toxicity*
  • Female
  • Fibrosis
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / pharmacology
  • Immunoglobulin G / genetics
  • Immunoglobulin G / pharmacology*
  • Immunosuppressive Agents / toxicity*
  • Mice
  • Mice, Inbred ICR
  • Nephritis, Interstitial / chemically induced*
  • Nephritis, Interstitial / pathology
  • Nephritis, Interstitial / prevention & control
  • Receptors, Transforming Growth Factor beta / blood
  • Receptors, Transforming Growth Factor beta / genetics*
  • Recombinant Fusion Proteins / pharmacology

Substances

  • Collagen Type IV
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Immunosuppressive Agents
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • Cyclosporine