Prevention of tissue injury by ribbon antisense to TGF-β1 in the kidney

Transforming growth factor-betal (TGF-beta 1) is an important mediator of glomerulosclerosis and tubulointerstitial fibrosis in renal diseases. We designed ribbon-type antisense oligos of TGF-beta 1, TGF-beta 1 RiAS, and combined them with a short peptide of the nuclear localization signal to form a transfection complex of DNA/peptide/liposomes (DPL) for enhanced cellular uptake. When H4IIE cells were transfected with TGF-beta 1 RiAS, the level of TGF-beta 1 mRNA was reduced by > 70%. We then examined the ratio of the kidney weight per body weight in rats. Whereas the weight ratio was 0.47% for the normal kidney, the ratio was 0.99% on day 5 after unilateral ureteric obstruction (UUO). The ratios were 0.95% with PBS injection, 1.07% with scrambled RiAS, and 0.68% with TGF-beta 1 RiAS. When examined for TGF-beta 1 expression in the tissue. the level of TGF-beta 1 mRNA was also significantly reduced following treatment with TGF-beta 1 RiAS. Further, physical changes such as diminished dilation, atrophy, as well as apoptosis caused by UUO were also found to be markedly reduced by TGF-beta 1 RiAS. The results show that ribbon antisense to TGF-beta 1 when combined with efficient uptake can effectively block TGF-beta 1 expression and preserve tissue integrity in kidneys with UUO.