Delivery of plasmid DNA expressing small interference RNA for TGF-beta type II receptor by cationized gelatin to prevent interstitial renal fibrosis.
Renal interstitial fibrosis is the common pathway of chronic renal disease, while it causes end-stage renal failure. Transforming growth factor-beta (TGF-beta) is well recognized to be one of the primary mediators to induce accumulation of extracellular matrix (ECM) in the fibrotic area. Therefore, it is expected that local suppression of TGF-beta receptor (TGF-betaR) is one of the crucial strategies for anti-fibrotic therapy. The objective of this study is to investigate feasibility of small interference RNA (siRNA) for TGF-betaR in the selective degradation of TGF-betaR mRNAs, resulting in fibrotic inhibition. A plasmid DNA of TGF-betaR siRNA expression vector with or without complexation of a cationized gelatin was injected to the left kidney of mice via the ureter. Unilateral ureteral obstruction (UUO) was performed for the injected mice to evaluate the anti-fibrotic effect. The injection of plasmid DNA-cationized gelatin complex significantly decreased the level of TGF-betaR and alpha-smooth muscle actin (alpha-SMA) over-expression, the collagen content of mice kidney, and the fibrotic area of renal cortex, in contrast to free plasmid DNA injection. It is concluded that retrograde injection of TGF-betaR siRNA expression vector plasmid DNA complexed with the cationized gelatin is available to suppress progression of renal interstitial fibrosis.
Kushibiki
Toshihiro
T
Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Nagata-Nakajima
Natsuki
N
Sugai
Manabu
M
Shimizu
Akira
A
Tabata
Yasuhiko
Y
D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D005079:Excipients; D005355:Fibrosis; D005780:Gelatin; D015870:Gene Expression; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009395:Nephritis, Interstitial / Q000473:pathology / Q000517:prevention & control*; D010957:Plasmids / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering / Q000096:biosynthesis*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis; D016707:Tissue Fixation
D005079:Excipients; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D005780:Gelatin; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II