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

The evidence that transforming growth factor-β (TGF-β) is a key mediator in the pathogenesis of fibrotic diseases is now supported by several lines of investigation. This evidence provides a certain base for targeting TGF-β as an antifibrotic agent.

We generated a chimeric cDNA, termed TGFβRII/Fc, encoding an extracellular domain of the TGF-β type II receptor fused to the IgG-Fc domain, and tested whether TGFβRII/Fc could be a novel strategy for treating glomerular diseases.

In cultured BNul-7 cells, recombinant TGFβRII/Fc reversed the antiproliferative response induced by TGF-β1. In addition, TGFβRII/Fc diminished the TGF-β1–induced production of EIIIA-positive fibronectin in cultured normal rat kidney cells. We then introduced the chimeric cDNA into the muscle of the nephritic rats by the hemagglutinating virus of Japan liposome–mediated gene transfer method in order to block the TGF-β activity in nephritic glomeruli through systemic delivery of chimeric molecules. Treatment with TGFβRII/Fc gene transfection could suppress the glomerular TGF-β mRNA in nephritic rats with a comparable effect in the reduction of extracellular matrix accumulation.

GFβRII/Fc successfully inhibited the action of TGF-β in vitro and in vivo, and gene therapy by chimeric TGFβRII/Fc might be feasible for the therapy of glomerulosclerosis.