INHIBITION OF TGF-BETA-1 EXPRESSION BY ANTISENSE OLIGONUCLEOTIDES SUPPRESSED EXTRACELLULAR-MATRIX ACCUMULATION IN EXPERIMENTAL GLOMERULONEPHRITIS

Overproduction of transforming growth factor-beta 1 (TGF-beta 1) has b een implicated in the pathogenesis of fibrotic diseases. TGF-beta 1 pl ays a crucial role in the accumulation of extracellular matrix (ECM) i n human and experimental glomerular diseases. However, it remains uncl ear whether inhibition of TGF-beta 1 overproduction would suppress TGF -beta 1 induced ECM accumulation. To inhibit the overproduction of TGF -beta 1 in experimental glomerulonephritis induced by anti-Thy 1.1 ant ibody, we introduced antisense oligodeoxynucleotides (ODN) for TGF-bet a 1 into the nephritic kidney by the HVJ-liposome-mediated gene transf er method. Sense, scrambled or reverse ODN were also introduced as con trols. Transfected ODN accumulated mainly in the nuclei of mesangial c ells in the glomeruli of transfected kidneys. In the antisense ODN-tra nsfected rats, a marked decrease in expression of TGF-beta 1 mRNA was confirmed by Northern analysis. Consequently, the expression of TGF-be ta 1 protein in the glomerulus was markedly reduced in the antisense O DN-transfected kidney with a comparable effect in preventing glomerula r ECM expansion in experimental glomerulonephritis. In contrast, sense , scrambled and reverse ODNs failed to suppress TGF-beta 1 expression and ECM accumulation. Thus, these results suggested that inhibition of TGF-beta 1 overproduction could suppress progression to glomeruloscle rosis.