Suppression Of Cyclosporine A Nephrotoxicity In Vivo By Transforming Growth Factor-β Receptor Ⅱ-IgG Fc Chimeric Protein

Background. Transforming growth factor β (TGFβ) is implicated in the pathogenesis of cyclosprine A (CsA) nephrotoxicity. We examined the efficacy of TGFβ RII/IgG Fc, a soluble chimeric protein of the extracellular domain of human TGFβ type II receptor and IgGl Fc, on CsA nephrotoxicity in mice.Methods. Subcutaneous injection of CsA (25 mg/kg/day) was given daily to mice maintained on low sodium diet. On day 1 and 7, an expression vector carrying cDNA for either TGF RII/IgG Fc or β-galactosidase was transfected into the skeletal muscles by electroporation. At 2 or 3 weeks of CsA treatment, and plasma and renal TGF β1 levels, and tubulointerstitial injury and fibrosis were evaluated. Results. By 2 weeks of CsA administration, plasma and renal TGFβ1 levels increased to maximum and, thereafter, declined toward the baseline levels. Renal TGFP lmRNA remained elevated until 3 weeks. Tubulointerstitial alterations became appreciable in 2 weeks and intensified by 3 weeks. At 2 weeks, the TGFβ RII/IgG Fc intervention abolished the increase in plasma TGFβ 1, attenuated the increase in renal TGFβl by 50%, and markedly suppressed the histological alterations. At 3 weeks, the histological alterations remained markedly suppressed by the intervention, with no appreciable effects on the renal TGFβlmRNA and protein.Conclusion. Introduction of TGF β RII/IgG Fc by gene transfer effectively abrogated CsA-induced tubulointerstitial alterations. Suppression of tubulointerstitial changes was evident at 3 weeks when renal TGFP 1 mRNA and protein were comparable to those with CsA alone, suggesting that early...