Background. Coexisting metabolic syndrome (MetS) and renal artery stenosis (RAS) are linked to poor renal outcomes. Mesenchymal stem/stromal cell- (MSC-) derived extracellular vesicles (EVs) from lean animals show superior ability to repair the experimental MetS+RAS kidney compared to EVs from MetS pig MSCs. We hypothesized that MetS leads to selective packaging in porcine EVs of microRNAs capable of targeting mitochondrial genes, interfering with their capacity to repair the MetS+RAS kidney. Methods. Five groups of pigs ( each) were studied after 16 weeks of diet-induced MetS and RAS (MetS+RAS) and MetS+RAS 4 weeks after a single intrarenal delivery of EVs harvested from allogeneic adipose tissue-derived MSCs isolated from Lean or MetS pigs, and Lean or MetS sham controls. Single-kidney blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multidetector CT, whereas EV microRNA cargo, renal tubular mitochondrial structure and bioenergetics, and renal injury pathways were assessed ex vivo. Results. microRNA sequencing revealed 19 dysregulated microRNAs capable of targeting several mitochondrial genes in MetS-EVs versus Lean-EVs. Lean- and MetS-EVs were detected in the stenotic kidney 4 weeks after administration. However, only MetS-EVs failed to improve renal mitochondrial density, structure, and function or attenuate oxidative stress, tubular injury, and fibrosis. Furthermore, Lean-EVs but not MetS-EVs restored RBF and GFR in MetS+RAS. Conclusion. MetS alters the cargo of mitochondria-related microRNAs in swine MSC-derived EVs, which might impair their capacity to repair the poststenotic kidney in MetS+RAS. These observations may contribute to develop approaches to improve the efficacy of MSC-EVs for patients with MetS.

中文翻译：

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代谢综合征改变了猪间充质干细胞衍生的细胞外囊泡中线粒体相关 microRNA 的货物，削弱了它们修复狭窄肾脏的能力

背景。并存的代谢综合征 (MetS) 和肾动脉狭窄 (RAS) 与肾脏预后不良有关。与来自 MetS 猪 MSCs 的 EVs 相比，来自瘦肉动物的间充质干/基质细胞 (MSC-) 衍生的细胞外囊泡 (EVs) 显示出更好的修复实验性 MetS+RAS 肾脏的能力。我们假设 MetS 会导致能够靶向线粒体基因的 microRNA 在猪 EV 中选择性包装，从而干扰它们修复 MetS+RAS 肾脏的能力。方法。五组猪（16 周饮食诱导的 MetS 和 RAS (MetS+RAS) 和 MetS+RAS 后 4 周进行研究，这些 EVs 是从 Lean 或 MetS 猪分离的同种异体脂肪组织来源的 MSCs 收获的 EV 单次肾内递送，以及 Lean 或MetS 假控制。用多层螺旋 CT 在体内评估单肾血流 (RBF) 和肾小球滤过率 (GFR)，而在体外评估 EV microRNA 货物、肾小管线粒体结构和生物能量学以及肾损伤途径。结果. microRNA 测序揭示了 19 种失调的 microRNA，它们能够靶向 MetS-EV 和 Lean-EV 中的多个线粒体基因。给药后 4 周，在狭窄的肾脏中检测到 Lean-和 MetS-EV。然而，只有 MetS-EVs 未能改善肾线粒体的密度、结构和功能或减弱氧化应激、肾小管损伤和纤维化。此外，Lean-EVs 而不是 MetS-EVs 恢复了 MetS+RAS 中的 RBF 和 GFR。结论。MetS 改变了猪 MSC 衍生 EV 中线粒体相关 microRNA 的货物，这可能会损害它们在 MetS+RAS 中修复狭窄后肾的能力。这些观察结果可能有助于开发提高 MSC-EV 对 MetS 患者疗效的方法。