Morishita Yoshiyuki, Imai Toshimi, Yoshizawa Hiromichi, Watanabe Minami, Ishibashi Kenichi, Muto Shigeaki, Nagata Daisuke
Division of Nephrology, Department of Medicine, Jichi Medical University, Tochigi, Japan.
Department of Medical Physiology, Meiji Pharmaceutical University, Tokyo, Japan.
Int J Nanomedicine. 2015 May 11;10:3475-88. doi: 10.2147/IJN.S82587. eCollection 2015.
Renal fibrosis is the final common pathway leading to end-stage renal disease. Although microRNA (miR) was recently shown to be involved in the development of renal fibrosis, few studies have focused on the effects on renal fibrosis of exogenous miR delivered in an in vivo therapeutic setting. The study reported here investigated the effects of miR-146a delivery using polyethylenimine nanoparticles (PEI-NPs) on renal fibrosis in vivo. PEI-NPs bearing miR-146 or control-miR (nitrogen/phosphate ratio: 6) were injected into the tail vein of a mouse model of renal fibrosis induced by unilateral ureteral obstruction. PEI-NPs bearing miR-146 significantly enhanced miR-146a expression in the obstructed kidney compared with the control group, while inhibiting the renal fibrosis area, expression of alpha-smooth muscle actin, and infiltration of F4/80-positive macrophages into the obstructed kidney. In addition, PEI-NPs bearing miR-146a inhibited the transforming growth factor beta 1-Smad and tumor necrosis factor receptor-associated factor 6-nuclear factor kappa B signaling pathways. Control-miR-PEI-NPs did not show any of these effects. These results suggest that the delivery of miR-146a attenuated renal fibrosis by inhibiting pro-fibrotic and inflammatory signaling pathways and that the delivery of appropriate miRs may be a therapeutic option for preventing renal fibrosis in vivo.
肾纤维化是导致终末期肾病的最终共同途径。尽管最近有研究表明微小RNA（miR）参与了肾纤维化的发展，但很少有研究关注在体内治疗环境中递送外源性miR对肾纤维化的影响。本文报道的研究探讨了使用聚乙烯亚胺纳米颗粒（PEI-NPs）递送miR-146a对体内肾纤维化的影响。将携带miR-146或对照miR（氮/磷比：6）的PEI-NPs注入单侧输尿管梗阻诱导的肾纤维化小鼠模型的尾静脉。与对照组相比，携带miR-146的PEI-NPs显著增强了梗阻肾脏中miR-146a的表达，同时抑制了肾纤维化面积、α-平滑肌肌动蛋白的表达以及F4/80阳性巨噬细胞向梗阻肾脏的浸润。此外，携带miR-146a的PEI-NPs抑制了转化生长因子β1-Smad和肿瘤坏死因子受体相关因子6-核因子κB信号通路。对照miR-PEI-NPs未显示出任何这些作用。这些结果表明，递送miR-146a通过抑制促纤维化和炎症信号通路减轻了肾纤维化，并且递送合适的miRs可能是体内预防肾纤维化的一种治疗选择。
