Atractylodes lancea and Magnolia officinalis combination protects against high fructose-impaired insulin signaling in glomerular podocytes through upregulating Sirt1 to inhibit p53-driven miR-221
Atractylodes lancea and Magnolia officinalis combination protects against high fructose-impaired insulin signaling in glomerular podocytes through upregulating Sirt1 to inhibit p53-driven miR-221
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白术和厚朴组合通过上调 Sirt1 抑制 p53 驱动的 miR-221，防止肾小球足细胞中高果糖受损的胰岛素信号传导
DOI：
10.1016/j.jep.2022.115688
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发表时间：
2022-09-15
影响因子：
5.4
通讯作者：
Kong, Ling-Dong
中科院分区：
文献类型：
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作者：
Yang, Jie;Wang, Zi-Xuan;Kong, Ling-Dong
民族药理学相关性：中医认为，长期饮食不当会导致湿邪，扰乱脏腑功能，包括肾虚。白术 (Atr) 和厚朴 (Mag) 作为著名药对，常用于化湿，具有护肾作用。研究目的：探讨Atr和Mag如何预防高果糖喂养引起的肾小球足细胞胰岛素信号损伤，这是肾小球足细胞功能障碍中胰岛素抵抗的主要因素。材料和方法：液相色谱-串联质谱(LC-MS/MS)分析Atr 和 Mag 的成分。体内采用10%果糖饮用水诱导大鼠模型，体外将热敏人足细胞（HPC）暴露于5 mM果糖。用不同剂量的Atr、Mag或Atr和Mag组合处理动物或培养的足细胞模型。通过Western blot、qRT-PCR和免疫荧光等实验分别检测大鼠肾小球或HPC中脂联素受体蛋白1（AdipoR1）、蛋白激酶B（AKT）、Sirt1、p53和miR-221的水平。结果：Atr和Mag组合中鉴定出55种成分。网络药理学分析表明Atr和Mag联合可能影响胰岛素信号通路。这种组合显着改善了高果糖喂养大鼠的全身胰岛素抵抗并防止了肾小球形态损伤。值得注意的是，高果糖会降低大鼠肾小球和培养的足细胞中的 IRS1、AKT 和 AdipoR1。使用 Sirt1 抑制剂/激动剂、p53 激动剂/抑制剂或 miR-221 模拟物/抑制剂培养的足细胞的进一步数据表明，高果糖下调 Sirt1 以刺激 p53 驱动的 miR-221，导致胰岛素信号传导损伤。在体内和体外模型中，Atr 和 Mag 组合可有效增加 Sirt1，并减少 p53 和 miR-221。结论：Atr 和 Mag 组合可能通过上调 Sirt1 抑制 p53 驱动的 miR-221 改善高果糖刺激的肾小球足细胞中的胰岛素信号传导。因此，这种组合对 Sirt1/p53/miR-221 的调节可能是足细胞胰岛素信号传导损伤的潜在治疗方法。
Ethnopharmacological relevance: In traditional Chinese medicine, a long term of improper diet causes the Dampness and disturbs Zang-Fu's functions including Kidney deficiency. Atractylodes lancea (Atr) and Magnolia officinalis (Mag) as a famous herb pair are commonly used to transform Dampness, with kidney protection.Aim of the study: To explore how Atr and Mag protected against insulin signaling impairment in glomerular podocytes induced by high dietary fructose feeding, a major contributor for insulin resistance in glomerular podocyte dysfunction.Materials and methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyze constituents of Atr and Mag. Rat model was induced by 10% fructose drinking water in vivo, and heat-sensitive human podocyte cells (HPCs) were exposed to 5 mM fructose in vitro. Animal or cultured podocyte models were treated with different doses of Atr, Mag or Atr and Mag combination. Western blot, qRT-PCR and immunofluorescence assays as well as other experiments were performed to detect adiponectin receptor protein 1 (AdipoR1), protein kinase B (AKT), Sirt1, p53 and miR-221 levels in rat glomeruli or HPCs, respectively.Results: Fifty-five components were identified in Atr and Mag combination. Network pharmacology analysis indicated that Atr and Mag combination might affect insulin signaling pathway. This combination significantly improved systemic insulin resistance and prevented glomerulus morphological damage in high fructose-fed rats. Of note, high fructose decreased IRS1, AKT and AdipoR1 in rat glomeruli and cultured podocytes. Further data from cultured podocytes with Sirt1 inhibitor/agonist, p53 agonist/inhibitor, or miR-221 mimic/inhibitor showed that high fructose downregulated Sirt1 to stimulate p53-driven miR-221, resulting in insulin signaling impairment. Atr and Mag combination effectively increased Sirt1, and decreased p53 and miR-221 in in vivo and in vitro models.Conclusions: Atr and Mag combination improved insulin signaling in high fructose-stimulated glomerular podocytes possibly through upregulating Sirt1 to inhibit p53-driven miR-221. Thus, the regulation of Sirt1/p53/miR-221 by this combination may be a potential therapeutic approach in podocyte insulin signaling impairment.