The Effect of Ribbon-Type Antisense Oligodeoxynucleotides for Transforming Growth Factor-beta1 in Unilateral Ureteral Obstruction

ABSTRACT

BACKGROUND: In unilateral ureteral obstruction (UUO), the obstructed kidney is characterized by interstitial fibrosis and an increase in transforming growth factor (TGF)-beta1. Interstitial expression of TGF-beta1 is important in tublointerstitial fibrosis. The objectives of this study is to make new ribbon-type antisense oligodeoxynucleotides (ODN) for TGF-beta1 which are resistant to exonuclease and to examine the effcets of TGF-beta1 on reducing tubulointerstitial fibrosis of the kidney. METHODS: We introduced a new ribbon-type antisense ODN for TGF-beta1 in rats using the UUO model to block interstitial fibrosis by tail vein injection. A combination of one antisense sequences for TGF-beta1 was adopted to construct a large antisense molecule with a loop and stem. Artificial viral envelope (AVE)-type hemagglutinating virus of Japan (HVJ)-liposomes were used as a vector system for the delivery of antisense ODN. RESULTS: The levels of TGF-beta1 mRNA was decreased more in the cultured mesangial cells treated with ribbon-type antisense ODN than in that of a linear-type antisense ODN for TGF-beta1. TGF-beta1 mRNA was increased markedly in the interstitium of untreated obstructed kidneys. Northem analysis revealed that the levels of TGF-beta1 mRNA were decreased in the obstructed kidneys treated with antisense ODN. The fibrosis of the obstructed kidneys treated with ribbon-type antisense ODN was dramatically less than that of the untreated group. CONCLUSIONS: These results demonstrate that the introduction of new ribbon-type antisense ODN for TGF-beta1 may be a potential therapeutic maneuver for preventing interstitial fibrosis.