Iekuni Ichikawa
Last active: 1/25/2012

Suppression of cyclosporine a nephrotoxicity in vivo by transforming growth factor beta receptor-immunoglobulin G chimeric protein.

Xin J, Homma T, Matsusaka T, Ma J, Isaka Y, Imai E, Ichikawa I
Transplantation. 2004 77 (9): 1433-42

PMID: 15167603 · DOI:10.1097/01.tp.0000121502.60664.ab

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.

MeSH Terms (13)

Animals Collagen Type IV Cyclosporine Female Fibrosis Immunoglobulin Fc Fragments Immunoglobulin G Immunosuppressive Agents Mice Mice, Inbred ICR Nephritis, Interstitial Receptors, Transforming Growth Factor beta Recombinant Fusion Proteins

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