Delivery of plasmid DNA expressing small interference RNA for TGF-β 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 extracelluar matrix (ECM) in the fibrotic area. Therefore, it is expected that local suppression of TGF-beta receptor (TGF-beta R) 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-beta R in the selective degradation of TGF-beta R mRNAs, resulting in fibrotic inhibition. A plasmid DNA of TGF-beta R 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-beta R 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-beta R siRNA expression vector plasmid DNA complexed with the cationized gelatin is available to suppress progression of renal interstitial fibrosis. (c) 2005 Elsevier B.V. All rights reserved.