Gene therapy by transforming growth factor-beta receptor-IgG Fc chimera suppressed extracellular matrix accumulation in experimental glomerulonephritis

Background. The evidence that transforming growth factor-beta (TGF-beta) is a key mediator in the pathogenesis of fibrotic diseases is now supported b y several lines of investigation. This evidence provides a certain base for targeting TGF-beta as an antifibrotic agent. Methods. We generated a chimeric cDNA, termed TGF beta RIL/Fc, encoding an extracellular domain of the TGF-beta type II receptor fused to the IgG-Fc d omain, and tested whether TGF beta RII/Fc could be a novel strategy for tre ating glomerular diseases. Results. In cultured BNul-7 cells, recombinant TGF beta RII/Fc reversed the antiproliferative response induced by TGF-beta 1. In addition, TGF beta RI I/Fc diminished the TGF-beta 1-induced production of EIIIA-positive fibrone ctin in cultured normal rat kidney cells. We then introduced the chimeric c DNA into the muscle of the nephritic rats by the hemagglutinating virus of Japan liposome-mediated gene transfer method in order to block the TGF-beta activity in nephritic glomeruli through systemic delivery of chimeric mole cules. Treatment with TGF beta RII/Fc gene transfection could suppress the glomerular TGF-beta mRNA in nephritic rats with a comparable effect in the reduction of extracellular matrix accumulation. Conclusion. TGF beta RII/Fc successfully inhibited the action of TGF-beta i n vitro and in vivo, and gene therapy by chimeric TGF beta RII/Fc might be feasible for the therapy of glomerulosclerosis.