High-Phosphate-Stimulated Macrophage-Derived Exosomes Promote Vascular Calcification via let-7b-5p/TGFBR1 Axis in Chronic Kidney Disease.
High-Phosphate-Stimulated Macrophage-Derived Exosomes Promote Vascular Calcification via let-7b-5p/TGFBR1 Axis in Chronic Kidney Disease.
复制标题
高磷酸盐刺激的巨噬细胞衍生的外泌体通过 let-7b-5p/TGFBR1 轴促进慢性肾脏病中的血管钙化
作者：
尽管巨噬细胞浸润已被证明可增加慢性肾病（CKD）患者的钙化动脉中膜，但巨噬细胞参与血管钙化（VC）进展的机制仍不清楚。利用miRNA-seq、RNA-seq、双荧光素酶报告基因测定、qRT-PCR和CKD患者以及CKD小鼠模型的动脉，我们鉴定了高磷酸盐刺激的巨噬细胞来源的外泌体（Mexo-P）抑制VSMC中let-7 b-5 p的表达，其进一步上调TGFBR 1。此外，使用功能获得和丧失分析来确定let-7 b-5 p和TGFBR 1对VC的调节作用和下游机制。机械地，Mexo-P通过抑制let-7 b-5 p诱导VSMC TGFBR 1上调，这进一步放大SMAD 3/RUNX 2信号传导，从而有助于VC。我们的研究结果表明，巨噬细胞来源的外泌体通过let-7 b-5 p/TGFBR 1轴在高磷酸盐条件下促进CKD相关VC。我们的研究提供了深入了解与VC相关的巨噬细胞，这可能是VC的潜在治疗靶点。
Although macrophage infiltration has been proven to increase calcified artery media in chronic kidney disease (CKD) patients, the mechanism by which macrophages are involved in vascular calcification (VC) progression remains unclear. Taking advantage of miRNA-seq, RNA-seq, dual-luciferase reporter assay, qRT-PCR, and arteries from CKD patients as well as CKD mouse models, we identified that high-phosphate-stimulated macrophage-derived exosomes (Mexo-P) suppressed let-7b-5p expression in VSMCs, which further upregulated TGFBR1. Moreover, gain-and-loss-of-function assays were used to determine the regulatory effects and downstream mechanism of let-7b-5p and TGFBR1 on VC. Mechanically, Mexo-P induced VSMC TGFBR1 upregulation by suppressing let-7b-5p, which further amplifies SMAD3/RUNX2 signaling and thereby contributes to VC. Our findings indicate that macrophage-derived exosomes promote CKD-associated VC through the let-7b-5p/TGFBR1 axis in high-phosphate conditions. Our study provides insight into macrophages associated with VC, which might be potential therapeutical targets for VC.
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