Transforming growth factor-beta 1 antisense oligodeoxynucleotides block interstitial fibrosis in unilateral ureteral obstruction.
BACKGROUND
Interstitial expression of transforming growth factor-beta1 (TGF-beta1) is important in tubulointerstitial fibrosis, a common process in most progressive renal diseases. However, no effective therapy for progressive interstitial fibrosis is known. Recently, we developed an artificial viral envelope (AVE)-type hemagglutinating virus of Japan (HVJ) liposome-mediated retrograde ureteral gene transfer method, which allowed us to introduce the genetic material selectively into renal interstitial fibroblasts.


METHODS
We introduced antisense or scrambled oligodeoxynucleotides (ODNs) for TGF-beta 1 into interstitial fibroblasts in rats with unilateral ureteral obstruction, a model of interstitial fibrosis, to block interstitial fibrosis by retrograde ureteral injection of AVE-type HVJ liposomes.


RESULTS
TGF-beta 1 and type I collagen mRNA increased markedly in the interstitium of untreated obstructed kidneys, and those were not affected by scrambled ODN transfection. Northern analysis and in situ hybridization revealed that the levels of TGF-beta 1 and type I collagen mRNA were dramatically decreased in antisense ODN-transfected obstructed kidneys. Consequently, the interstitial fibrotic area of the obstructed kidneys treated with antisense ODN was significantly less than that of the obstructed kidneys untreated or treated with scrambled ODN.


CONCLUSIONS
The introduction of TGF-beta 1 antisense ODN into interstitial fibroblasts may be a potential therapeutic maneuver for interstitial fibrosis.
Isaka
Y
Y
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan. kidney@medone.med.osaka-u.ac.jp
Tsujie
M
M
Ando
Y
Y
Nakamura
H
H
Kaneda
Y
Y
Imai
E
E
Hori
M
M
D000199:Actins / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis / Q000517:prevention & control; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014517:Ureteral Obstruction / Q000473:pathology*
D000199:Actins; D016376:Oligonucleotides, Antisense; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen