Nup155 的缺失会抑制 INO80 mRNA 的核输出,从而促进高果糖驱动的荚膜衰老。

Li Chen, Tangdi Xu, Zixuan Wang, Chengzhi Wang, Lei Fang, Lingdong Kong
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引用次数: 0

摘要

引言荚膜衰老会导致荚膜丧失和肾小球病变。摄入过量果糖是导致荚膜损伤的一个危险因素。然而,高果糖是否会促进荚膜细胞衰老仍是一个未知数:探索高果糖促使荚膜衰老的病理机制,并寻找缓解荚膜衰老的天然化合物:方法:通过衰老相关的β-半乳糖苷酶(SA-β-gal)染色、Western印迹、实时定量聚合酶链反应(qRT-PCR)、彗星试验和免疫荧光对荚膜衰老进行表征。蛋白质组学分析用于鉴定高果糖暴露荚膜细胞中不同表达的蛋白质。透射电子显微镜观察了荚膜细胞核孔复合体(NPC)和足过程。通过 qRT-PCR、Western 印迹和免疫荧光检测了核蛋白 155(Nup155)和肌醇需要突变体 80(INO80)的 mRNA 和蛋白质水平。进行了虚拟筛选,以寻找针对 Nup155 的天然化合物:结果:高果糖增加了大鼠肾小球和荚膜细胞中 SA-β-gal 活性、p53、p21、p16 和磷酸化组蛋白 H2AX(γ-H2AX)的蛋白水平,以及白细胞介素-1β(IL-1β)、IL-6 和肿瘤坏死因子α(TNF-α)的 mRNA 表达。蛋白质组分析揭示了一个关键分子 Nup155,该分子在高果糖诱导的荚膜衰老中减少。同时,体内和体外荚膜细胞 NPCs 的数量也减少了。高果糖抑制了 INO80 mRNA 的核输出,从而下调了荚膜衰老中 INO80 蛋白的表达。缺失 Nup155 可抑制 INO80 mRNA 核输出以诱导荚膜衰老,而过表达 Nup155 或 INO80 则可缓解高果糖诱导的荚膜衰老。研究发现阿魏酸可通过直接结合稳定 Nup155 蛋白和增强其转录来上调 Nup155,从而促进 INO80 mRNA 核输出,缓解高果糖诱导的荚膜衰老:结论:高果糖通过减少 Nup155 来抑制 INO80 mRNA 核输出,从而诱导荚膜衰老。以 Nup155 为靶点的阿魏酸可能是防止高果糖诱导的荚膜衰老的一种潜在策略。
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Loss of Nup155 promotes high fructose-driven podocyte senescence by inhibiting INO80 mRNA nuclear export.

Introduction: Podocyte senescence causes podocyte loss and glomerulopathy. Excessive fructose intake is a risk factor for podocyte injury. However, whether high fructose promotes podocyte senescence remains unknown.

Objectives: To explore the pathological mechanism by which high fructose drives podocyte senescence and find natural compounds to alleviate podocyte senescence.

Methods: Podocyte senescence was characterized with senescence-associated beta-galactosidase (SA-β-gal) staining, Western blot, real-time quantitative polymerase chain reaction (qRT-PCR), comet assay and immunofluorescence. Proteomics analysis was performed to identify differentially expressed proteins in high fructose-exposed podocytes. Podocyte nuclear pore complexes (NPCs) and foot processes were observed by transmission electron microscopy. The mRNA and protein levels of nucleoporin 155 (Nup155) and inositol requiring mutant 80 (INO80) were detected by qRT-PCR, Western blot and immunofluorescence. Virtual screening was conducted to find natural compounds that target Nup155.

Results: High fructose increased SA-β-gal activity, protein level of p53, p21, p16 and phosphorylated histone H2AX (γ-H2AX), as well as mRNA expression of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor α (TNF-α) in rat glomeruli and podocytes. Proteomic analysis unraveled a crucial molecule Nup155, which was decreased in high fructose-induced podocyte senescence. Meanwhile, the number of podocyte NPCs was also decreased in vivo and in vitro. Consistently, high fructose suppressed nuclear export of INO80 mRNA, thereby down-regulated INO80 protein expression in podocyte senescence. Deletion of Nup155 inhibited INO80 mRNA nuclear export to induce podocyte senescence, whereas overexpression of Nup155 or INO80 alleviated high fructose-induced podocyte senescence. Ferulic acid was found to up-regulate Nup155 by both direct binding to stabilize Nup155 protein and enhancing its transcription, to promote INO80 mRNA nuclear export in the mitigation of high fructose-caused podocyte senescence.

Conclusion: High fructose induces podocyte senescence by decreasing Nup155 to inhibit INO80 mRNA nuclear export. Ferulic acid targeting Nup155 may be a potential strategy to prevent high fructose-induced podocyte senescence.

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