| 邰千慧,张 静,米白冰,石 静,惠晓丽,陈 欢,许 静,崔 巍.脂肪细胞衰老通过衰老相关分泌表型诱导微血管内皮细胞早衰和功能紊乱[J].现代生物医学进展英文版,2022,(14):2625-2630. |
| 脂肪细胞衰老通过衰老相关分泌表型诱导微血管内皮细胞早衰和功能紊乱 |
| Adipocyte Senescence Induces Microvascular Endothelial Progeria and Functional Disorder through Senescence Associated Secretory Phenotype |
| Received:January 25, 2022 Revised:February 21, 2022 |
| DOI：10.13241/j.cnki.pmb.2022.14.005 |
| 中文关键词: 脂肪细胞 细胞衰老 衰老相关分泌表型 糖尿病肾病 |
| 英文关键词: Adipocytes Cellular senescence Senescence-associated secretory phenotype Diabetic kidney disease |
| 基金项目:国家自然科学基金项目（82103213）；西安交通大学第一附属医院院基金（2020ZYTS-16） |
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| 中文摘要: |
| 摘要 目的：探讨衰老脂肪细胞对微循环内皮细胞（ECs）功能状态的影响，以及异常早衰在糖尿病肾病（DKD）中的潜在作用。方法：3T3-L1细胞被诱导分化为年轻和衰老的脂肪细胞。HMEC-1细胞分别培养在年轻、衰老脂肪细胞制成的条件培养基和对照培养基中。通过免疫荧光检测γH2AX和SA-β-半乳糖苷酶活性鉴定细胞衰老状态。通过qPCR、Western blot检测衰老相关分泌表型（SASP）、胰岛素受体底物1（IRS1）、Jun原癌基因（JUN）、组蛋白H3第4位赖氨酸二甲基化、三甲基化（H3K4me2、H3K4me3）等指标的表达水平。利用GEO数据库对衰老肾脏和早期糖尿病肾病的差异表达基因（DGE）进行生物信息学分析。结果：衰老脂肪细胞的SASP表达显著升高，其条件培养基成功诱导HMEC-1细胞衰老。与年轻HMEC-1细胞相比，诱导衰老的HMEC-1细胞中斯钙素1（STC1）表达上调，前炎症因子、JUN和H3K4me3均表达下调。与对照组相比，IRS1在年轻HMEC-1细胞中显著下调，在诱导衰老的HMEC-1细胞中无显著变化。生物信息学结果显示差异基因的交集仅存在于衰老肾脏的上调基因和早期糖尿病肾病的下调基因之间。PPI网络分析、GO及KEGG富集分析表明IL6-SOCS3-IRS1是异常早衰机制参与早期DKD发生的核心信号通路。结论：脂肪细胞衰老导致微循环内皮细胞早衰并损害其正常功能状态，异常早衰机制参与了DKD的发生发展。 |
| 英文摘要: |
| ABSTRACT Objective: Diabetic kidney disease (DKD) is a world-wide health burden. Obesity and dyslipidemia are risk factors for DKD, yet the detailed mechanism is not well understood. High fat diet can lead to tissue senescence and increase of senescence-associated secretory phenotype (SASP). The study aimed to explore the progeria of endothelial cells (ECs) induced by senescent adipocytes and its consequent effects. Methods: 3T3-L1 cells were induced to differentiate to young and senescent adipocytes. HMEC-1 cells were cultured in the conditioned medium from young, senescent adipocytes and control medium. The senescent state was tested by immunofluorescence detection of γH2AX and SA-β-Galactosidase staining. The level of SASP, IRS1, JUN, H3K4me2, H3K4me3 were detected by qPCR and Western blot. Differential gene expression (DGE) of ageing kidney and early diabetic nephropathy on gene expression omnibus (GEO) were analyzed bioinformatically. Results: The level of SASP in senescent adipocytes increased significantly, and its conditioned medium successfully induced the senescence of HMEC-1 cells. Compared with young HMEC-1 cells, the expression of STC1 in induced senescent HMEC-1 cells was upregulated, and the expression of proinflammatory factors, JUN and H3K4me3 were downregulated. Compared with the control group, IRS1 was downregulated significantly in young HMEC-1 cells, and was not changed significantly in induced senescent HMEC-1 cells. Bioinformatics results showed that the intersection of DGE only existed between the upregulated genes of the ageing kidney and the downregulated genes of early diabetic nephropathy. PPI network, GO and KEGG enrichment analyses showed that IL6-SOCS3-IRS1 was the core signal pathway involved in the occurrence of early DKD. Conclusion: Adipocyte senescence leads to progeria of microcirculatory endothelial cells and impairs their normal function. Progeria mechanism is involved in the occurrence and development of DKD. |
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