Sustained-Release Rapamycin-Eluting Cobalt-Based Alloy Stent Ameliorates Ureteral Stricture in Mini-Pigs by Regulating TGF-β1/Smad3/mTOR/4EBP1/eIF4E Signaling Pathways.

Abstract

Purpose: To assess the feasibility and efficacy of sustained-release rapamycin-eluting metal stent in the repair of thermal injury-induced ureteral stricture in mini-pigs and explore its underlying mechanisms. Materials and Methods: A total of 18 female mini-pigs were used in this study. At 1 month after effective establishment of ureteral stricture model, they were randomly divided into normal control, model, bare-metal stent, and rapamycin-eluting stent groups. Before and at 4 weeks after stent placement, all animals underwent retrograde ureterography and single-photon emission computed tomography. Histologic examination was performed to assess the histomorphologic changes of the ureteral tissues. Real-time quantitative polymerase chain reaction and Western blot analysis were used to evaluate the expression levels of pro-fibrotic factors, transforming growth factor-beta1 (TGF-β1) and Smad3, as well as mammalian target of rapamycin (mTOR) downstream effectors, 4E binding protein 1 (4EBP1) and eukaryotic initiation factor 4E (eIF4E), in the ureteral stricture tissues. Results: Four weeks after stent placement, ureteral stricture was significantly ameliorated, and the glomerular filtration rate was significantly improved in the rapamycin-eluting stent group than the model and bare-metal stent groups (all p < 0.05). Pathologic examinations revealed obviously reduced fibroblasts and collagen fibers in the submucosa of the rapamycin-eluting stent group. The mRNA and protein expression levels of TGF-β1, Smad3, 4EBP1, and eIF4E were significantly decreased in the rapamycin-eluting stent group than the model and bare-metal stent groups (p < 0.05), whereas no significant difference was found between the model and bare-metal stent groups, indicating that rapamycin-eluting stent can inhibit fibroblast proliferation and attenuate fibrosis in the ureteral tissues. Conclusion: Sustained-release rapamycin-eluting stent can effectively ameliorate thermal injury-induced ureteral stricture in mini-pigs. The mechanism may be related to the role of rapamycin in inhibiting TGF-β1 and Smad3 expression, promoting the ureteral tissue remodeling through blocking mTOR, and suppressing 4EBP1 and eIF4E expression in the ureteral tissues. Sustained-release rapamycin-eluting stent deserves further investigation as a potentially effective means of treating iatrogenic ureteral strictures.