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 by 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 RII/Fc, encoding an extracellular domain of the TGF-beta type II receptor fused to the IgG-Fc domain, and tested whether TGF beta RII/Fc could be a novel strategy for treating 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 RII/Fc diminished the TGF-beta 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-beta activity in nephritic glomeruli through systemic delivery of chimeric molecules. 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.


CONCLUSIONS
TGF beta RII/Fc successfully inhibited the action of TGF-beta in vitro and in vivo, and gene therapy by chimeric TGF beta RII/Fc might be feasible for the therapy of glomerulosclerosis.
Isaka
Y
Y
First Department of Medicine, Osaka University School of Medicine, Japan.
Akagi
Y
Y
Ando
Y
Y
Tsujie
M
M
Sudo
T
T
Ohno
N
N
Border
W A
WA
Noble
N A
NA
Kaneda
Y
Y
Hori
M
M
Imai
E
E
D000818:Animals; D002678:Chimera / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D005240:Feasibility Studies; D015870:Gene Expression / Q000502:physiology; D015316:Genetic Therapy; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics* / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism