Cell Biology – Immunology – Pathology

Kidney International (2005) 67, 897–908; doi:10.1111/j.1523-1755.2005.00154.x

Effects of suppressing intrarenal angiotensinogen on renal transforming growth factor-bold beta1 expression in acute ureteral obstruction

GYU-TAE SHIN, WOOK-HWAN KIM, HYUNEE YIM, MYUNG-SUNG KIM and HEUNGSOO KIM

Department of Nephrology, Department of Surgery, and Department of Pathology, Ajou University School of Medicine, Suwon, South Korea

Correspondence: Gyu-Tae Shin, M.D., Ajou University School of Medicine, Department of Nephrology, Paldal-gu, Wonchon-dong, San 5, Suwon, South Korea, 442–749. E-mail:gtshin@ajou.ac.kr

Received 22 July 2004; Revised 8 September 2004; Accepted 20 September 2004.

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Abstract

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.

Conclusion

 

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.

Keywords:

angiotensinogen, antisense RNA, ureteral obstruction, TGF-beta1

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