편측성 요관 폐쇄모델에서 Transforming Growth Factor-β1 mRNA에 대한 리본형 Antisense Oligodeoxynucleotide의 유전자 치료 효과

Abstract

Background : In unilateral ureteral obstruction (UUO), the obstructed kidney is characterized by interstitial fibrosis and an increase in transforming growth factor (TGF)- 1. Interstitial expression of TGF- 1 is important in tublointerstitial fibrosis. The objectives of this study is to make new ribbon-type antisense oligodeoxynucleotides (ODN) for TGF- 1 which are resistant to exonuclease and to examine the effects of TGF- 1 on reducing tubulointerstitial fibrosis of the kidney. Methods : We introduced a new ribbon-type antisense ODN for TGF- 1 in rats using the UUO model to block interstitial fibrosis by tail vein injection. A combination of one antisense sequences for TGF- 1 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- 1 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- 1. TGF- 1 mRNA was increased markedly in the interstitium of untreated obstructed kidneys. Northern analysis revealed that the levels of TGF- 1 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- 1 may be a potential therapeutic maneuver for preventing interstitial fibrosis. Key Words : Models, Animal-Gene Therapy-Transforming Growth Factor-beta-Ureteral Obstruction