Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney.
There are currently no effective therapies for progressive fibrotic diseases. Recent evidence has implicated overproduction of transforming growth factor-beta1 (TGF-beta1) as a major cause of tissue fibrosis. Furthermore, this evidence implies that inhibitors of TGF-beta1 may be clinically useful as antifibrotic agents. The proteoglycan decorin is a known inhibitor of TGF-beta1. In a rat model of glomerulonephritis we have shown that fibrosis is mediated by TGF-beta1. We report here that transfer of decorin cDNA into rat skeletal muscle increases the amount of decorin messenger RNA and protein present in skeletal muscle and decorin present in kidney, where it has a marked therapeutic effect on fibrosis induced by glomerulonephritis. Transfected glomerulonephritic rats showed a significant reduction in levels of glomerular TGF-beta1 mRNA and TGF-beta1 protein, extracellular matrix accumulation and proteinuria. These results demonstrate the potential of gene therapy as a novel treatment for fibrotic diseases caused by TGF-beta1.
Isaka
Y
Y
Division of Nephrology, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
Brees
D K
DK
Ikegaya
K
K
Kaneda
Y
Y
Imai
E
E
Noble
N A
NA
Border
W A
WA
D000818:Animals; D058575:Decorin; D016326:Extracellular Matrix Proteins; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005921:Glomerulonephritis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D007668:Kidney / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
C546880:Dcn protein, rat; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans