HORMONES – CYTOKINES – SIGNALING
Kidney International (1999) 55, 465–475; doi:10.1046/j.1523-1755.1999.00275.x
Gene therapy by transforming growth factor-
receptor-IgG Fc chimera suppressed extracellular matrix accumulation in experimental glomerulonephritis
YOSHITAKA ISAKA, YOSHITAKA AKAGI, YUTAKA ANDO, MICHIKO TSUJIE, TETSUO SUDO, NORIKO OHNO, WAYNE A BORDER, NANCY A NOBLE, YASUFUMI KANEDA, MASATSUGU HORI and ENYU IMAI
First Department of Medicine, Osaka University School of Medicine, Osaka, Japan, Division of Nephrology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA, Division of Gene Therapy Science, Osaka University School of Medicine, Osaka, and Basic Research Labs., Toray Industries, Inc., Kamakura, Japan
Correspondence: Dr Enyu Imai, First Department of Medicine, Osaka University School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565–0871, Japan. E-mail: kidney@medone.med.osaka-u.ac.jp
Received 6 February 1998; Revised 2 September 1998; Accepted 3 September 1998.
Abstract
Gene therapy by transforming growth factor-
receptor-IgG Fc chimera suppressed extracellular matrix accumulation in experimental glomerulonephritis.
Background
The evidence that transforming growth factor-
(TGF-) 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- as an antifibrotic agent.
Methods
We generated a chimeric cDNA, termed TGFRII/Fc, encoding an extracellular domain of the TGF- type II receptor fused to the IgG-Fc domain, and tested whether TGFRII/Fc could be a novel strategy for treating glomerular diseases.
Results
In cultured BNul-7 cells, recombinant TGFRII/Fc reversed the antiproliferative response induced by TGF-1. In addition, TGFRII/Fc diminished the TGF-1–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- activity in nephritic glomeruli through systemic delivery of chimeric molecules. Treatment with TGFRII/Fc gene transfection could suppress the glomerular TGF- mRNA in nephritic rats with a comparable effect in the reduction of extracellular matrix accumulation.
Conclusion
GFRII/Fc successfully inhibited the action of TGF- in vitro and in vivo, and gene therapy by chimeric TGFRII/Fc might be feasible for the therapy of glomerulosclerosis.
Keywords:
TGF-, glomerulosclerosis, Thy-1 GN, fibrosis, injury, renal lesions
