Delivery of microRNA-146a with polyethylenimine nanoparticles inhibits renal fibrosis in vivo

Abstract

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.

Keywords:

• miR
• end-stage renal disease
• pro-fibrotic signaling pathway
• inflammatory signaling pathway

Supplementary material

Figure S1 Distribution of microRNA (miR)-polyethylenimine nanoparticles (PEI-NPs) in liver and spleen. Immunofluorescence analysis of systemically delivered Cy3-labeled miR-PEI-NPs in liver and spleen.

Abbreviation: DAPI, 4′,6-diamidino-2-phenylindole.

Acknowledgments

This work was supported by the Japanese Ministry of Education Culture, Sports, Science and Technology (MEXT)-Supported Program for Strategic Research Foundations at Private Universities (2013–2017) (grant number S1211029).

Author contributions

YM designed the study and coordinated the experiments, performed statistical analysis, and drafted the manuscript. HY performed all immunofluorescence analyses. MW performed all miR-PEI-NP injections and blood and tissue sampling. TI, KI, and SM participated in the study design. DN conceived the study and participated in its design and coordination. All authors contributed toward revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflicts of interest in this work.