Kushibiki Toshihiro, Nagata-Nakajima Natsuki, Sugai Manabu, Shimizu Akira, Tabata Yasuhiko
Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
J Control Release. 2005 Jul 20;105(3):318-31. doi: 10.1016/j.jconrel.2005.02.030.
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.
肾间质纤维化是慢性肾脏疾病的共同途径，最终会导致终末期肾衰竭。转化生长因子-β（TGF-β）被公认为是诱导纤维化区域细胞外基质（ECM）积聚的主要介质之一。因此，局部抑制TGF-β受体（TGF-βR）有望成为抗纤维化治疗的关键策略之一。本研究的目的是探讨小干扰RNA（siRNA）对TGF-βR在选择性降解TGF-βR mRNA从而抑制纤维化方面的可行性。将携带或不携带阳离子化明胶复合物的TGF-βR siRNA表达载体质粒DNA经输尿管注入小鼠左肾。对注射后的小鼠进行单侧输尿管梗阻（UUO）以评估抗纤维化效果。与游离质粒DNA注射相比，注射质粒DNA-阳离子化明胶复合物可显著降低TGF-βR和α-平滑肌肌动蛋白（α-SMA）的过表达水平、小鼠肾脏的胶原蛋白含量以及肾皮质的纤维化面积。结论是，逆行注射与阳离子化明胶复合的TGF-βR siRNA表达载体质粒DNA可有效抑制肾间质纤维化的进展。
