Effects of suppressing intrarenal angiotensinogen on renal transforming growth factor-beta1 expression in acute ureteral obstruction.
BACKGROUND
Angiotensin II (Ang II) mediates the up-regulation of fibrogenic factors such as transforming growth factor-beta1 (TGF-beta1) in chronic renal diseases. In addition, it has been proposed that the intrarenal renin-angiotensin system (RAS) is as important as the systemic RAS in kidney disease progression.


METHODS
We suppressed angiotensinogen (AGT) gene expression in the kidney by transferring recombinant adenoviral vectors carrying a transgene expressing AGT antisense mRNA, and determined the effect of the local inhibition of the RAS on TGF-beta1 synthesis in the kidneys of rats with unilateral ureteral obstruction (UUO). Immediately after UUO, recombinant adenovirus vectors were injected intraparenchymally into the cortex of obstructed kidneys.


RESULTS
beta-galactosidase (beta-gal)-stained kidney sections revealed the efficient transduction of the recombinant adenoviral vectors into tubular epithelial cells. Kidney cortex injected with AGT antisense showed significantly lower native AGT mRNA and protein expressions than control UUO kidneys at 24 hours and 5 days post-UUO. TGF-beta1 was significantly up-regulated in the renal cortex 24 hours and 5 days post-UUO, whereas AGT antisense-injected UUO rats showed significantly reduced TGF-beta1 expression compared to control UUO rats. Both fibronectin and collagen type I expressions were increased 24 hours and 5 days post-UUO, and these augmentations were considerably reduced by AGT antisense RNA treatment.


CONCLUSIONS
This study demonstrates that the suppression of intrarenal RAS prevents the formation of renal cortical TGF-beta1, and of related fibrogenic factors, in early UUO.
Shin
Gyu-Tae
GT
Department of Nephrology, Ajou University School of Medicine, Suwon, South Korea. gtshin@ajou.ac.kr
Kim
Wook-Hwan
WH
Yim
Hyunee
H
Kim
Myung-Sung
MS
Kim
Heungsoo
H
D000208:Acute Disease; D000808:Angiotensinogen / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D024042:Collagen Type I / Q000235:genetics; D005353:Fibronectins / Q000235:genetics; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D016372:RNA, Antisense / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D053773:Transforming Growth Factor beta1; D014517:Ureteral Obstruction / Q000378:metabolism*
D024042:Collagen Type I; D005353:Fibronectins; D016372:RNA, Antisense; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000808:Angiotensinogen