Delivery of plasmid DNA expressing small interference RNA for TGF- β type II receptor by cationized gelatin to prevent interstitial renal fibrosis

Abstract

Renal interstitial fibrosis is the common pathway of chronic renal disease, while it causes end-stage renal failure. Transforming growth factor- β (TGF- β) 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- β receptor (TGF- βR) 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- βR in the selective degradation of TGF- βR mRNAs, resulting in fibrotic inhibition. A plasmid DNA of TGF- βR 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- βR and α-smooth muscle actin ( α-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- βR siRNA expression vector plasmid DNA complexed with the cationized gelatin is available to suppress progression of renal interstitial fibrosis.