COMP与糖尿病肾病自噬相关性分析及其功能验证

doi:10.3969/j.issn.1674-8115.2024.07.006

摘要/Abstract

摘要：

目的·通过研究高糖环境下肾小球足细胞中软骨寡聚基质蛋白（cartilage oligomeric matrix protein，COMP）与自噬的关系，进一步阐明在高糖环境下足细胞受损的可能机制。方法·从GENE EXPRESSION OMNIBUS（GEO）数据库下载基因表达数据集GSE104948，使用GEO2R筛选差异表达基因（differentially expressed gene，DEG），并对筛选出来的DEG进行富集分析。将加权基因共表达网络分析（Weighted Gene Co-Expression Network Analysis，WGCNA）与STRING数据库构建 DEG的蛋白互作网络（protein protein interaction network，PPI）获得的相关性最高的关键基因（hub gene）取交集，并再次进行富集分析。体外培养条件永生性小鼠足细胞株，待其分化完全后，采用高糖刺激，Western blotting检测足细胞COMP、哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）、微管相关蛋白1A/1B-轻链3（microtubule-associated protein 1 light chain3，LC3/MAP1LC3）等蛋白的表达。进一步通过抑制COMP的shRNA慢病毒载体感染足细胞以抑制COMP表达，并通过嘌呤霉素筛选稳定株，经Western blotting检测稳定株COMP、mTOR、LC3的表达，以观察COMP对自噬的影响。结果·共筛选出362个DEG进行后续分析。在这些DEG中，284个基因上调，78个基因下调。基因本体论（Gene Onotology，GO）术语分析结果显示，糖尿病肾病（diabetic nephropathy，DN）数据集中的DEG主要富集于细胞表面受体信号通路、受体结合等。主要富集的京都基因和基因组数据库（Kyoto Encyclopedia of Genes and Genomes，KEGG）通路包括细胞因子?细胞因子受体相互作用、磷脂酰肌醇3-激酶（phosphatidylinositol 3-kinase，PI3K）/蛋白激酶B（protein kinase B，PKB/AKT）信号通路等。WGCNA和PPI两部分hub基因取交集，验证了64个hub基因，再次用KEGG注释hub基因，发现大部分hub基因富集在“细胞外基质（extracellular matrix，ECM）?受体相互作用”和“PI3K/AKT信号通路”。在64个hub基因中，COMP呈显著高表达（logFC>2），而PI3K/AKT/mTOR信号通路是经典的自噬通路，提示COMP可能通过该通路影响细胞自噬。Western blotting结果显示，与甘露醇对照组、低糖组比较，高糖刺激下足细胞COMP表达明显升高。与对照组相比，高糖组LC3-Ⅱ的水平明显降低，表明高糖环境下足细胞的自噬启动受到了抑制。与阴性对照相比，敲低COMP的小鼠肾足细胞LC3-Ⅱ水平明显升高，mTOR随着COMP水平的降低也有所下降，表明抑制COMP有助于足细胞的自噬恢复。结论·DN患者的COMP高表达，高度富集于ECM受体和PI3K/AKT信号通路。高糖环境下小鼠肾足细胞自噬受到抑制，高糖诱导的足细胞COMP高表达可能是自噬抑制的关键因素，抑制COMP有助于小鼠肾足细胞的自噬恢复。

关键词: 糖尿病肾病, 足细胞, 自噬, 生物信息学, 差异基因, 软骨寡聚基质蛋白（COMP）

Abstract:

Objective ·To further clarify the mechanism of podocyte damage by studying the expression of cartilage oligomeric matrix protein (COMP) in glomerular podocytes and its relationship with podocyte autophagy under high glucose environment. Methods ·The gene expression dataset GSE104948 was downloaded from the GENE EXPRESSION OMNIBUS (GEO) database, and differentially expressed genes (DEGs) were obtained via GEO2R. The molecular functions and signaling pathways related to differential genes were summarized. The most correlated key genes (hub genes) were acquired by Weighted Gene Co-Expression Network Analysis (WGCNA) and the protein-protein interaction network (PPI) of DEGs was constructed with STRING database. The enrichment analysis was performed again. Conditionally immortalized mouse podocyte cells were cultured in vitro. After being fully differentiated, they were stimulated with high glucose, and the expressions of COMP, mammalian target of rapamycin (mTOR), microtubule-associated protein 1 light chain3 (LC3) and other proteins in podocytes were detected by Western blotting. The shRNA constructed by lentiviral vector was further used to infect podocytes to inhibit the expression of COMP, and the stable cell strains were screened by puromycin. The expression of COMP, mTOR, and LC3 of stable strains were detected by Western blotting, in order to observe the effect of COMP on autophagy. Results ·A total of 362 DEGs were filtered for subsequent analysis. Among these DEGs, 284 genes were up-regulated and 78 genes were down-regulated. The results of Gene Onotology (GO) term analysis showed that DEGs in diabetic nephropathy (DN) were mainly enriched in cell surface receptor signaling pathway, receptor binding, etc. The main enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways included phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway, extracellular matrix (ECM)-receptor interaction, etc. Sixty-four hub genes were refined through the intersection of WGCNA and PPI hub genes, and the hub genes with significantly increased or decreased expression were sifted. The hub genes were annotated with KEGG again, and it was found that most of the hub genes were enriched in "ECM-receptor interaction" and "PI3K/AKT signaling pathway". The PI3K/AKT/mTOR signaling pathway is a classic autophagy pathway, and COMP was absolutely overexpressed (logFC>2) in the 64 hub genes, suggesting that it may affect autophagy through this pathway. Western blotting showed that compared with the mannitol control group and the low glucose group, the expression of COMP in podocytes was significantly increased under high glucose stimulation. Compared with the control group, the expression of LC3-II in the high glucose group was significantly decreased, indicating that the autophagy initiation of podocytes was inhibited under the high glucose environment. Compared with the negative control, the expression of LC3-II in renal podocytes of mice with knockdown of COMP was significantly increased, and the mTOR decreased with the decrease of the expression of COMP, indicating that inhibiting COMP contributed to the recovery of autophagy in podocytes. Conclusion ·COMP is highly expressed in DN patients and highly enriched in ECM receptor and PI3K/AKT signaling pathway. Autophagy in mouse renal podocytes is inhibited under high glucose conditions, and the high expression of COMP induced by high glucose may be a key factor in autophagy inhibition. Inhibiting COMP helps to restore autophagy in mouse renal podocytes.

Key words: diabetic nephropathy, podocyte, autophagy, bioinformatics, differential gene, cartilage oligomeric matrix protein (COMP)

中图分类号:

魏云鑫, 蒋绪顺, 蔡梦瑶, 温睿智, 杜晓刚. COMP与糖尿病肾病自噬相关性分析及其功能验证[J]. 上海交通大学学报（医学版）, 2024, 44(7): 847-858.

WEI Yunxin, JIANG Xushun, CAI Mengyao, WEN Ruizhi, DU Xiaogang. Correlation analysis of COMP and autophagy in diabetic nephropathy and its functional verification[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(7): 847-858.

图/表 6

图1 WGCNA和PPI筛选hub基因Note： A. Soft threshold (power). B. Cluster dendrogram. C. Eigengene adjacency heatmap. D. Protein protein interaction network.

Fig 1 Hub genes screened by WGCNA and PPI

图2 差异表达基因筛选Note： A. Volcano map of differential expression genes. B. Heat map of differential expression genes. C. Significantly different expression genes and their definitions.

Fig 2 Differential expression genes screening

图3 差异基因KEGG分析Note： A. KEGG enriched gene bubble chart. B. Four signaling pathways with the most differentially enriched genes and corresponding differential expression genes.

Fig 3 KEGG analysis of differential expression genes

图4 Hub基因富集分析Note： A. Biological process (BP). B. Cell localization (CC). C. Molecular function (MF). D. Signaling pathway (KEGG).

Fig 4 Hub gene enrichment analysis

图5 高糖诱导的COMP过表达并抑制自噬Note： A. The Western blotting results showed that compared with the mannitol control group and the LG group, the expression of COMP significantly increased under high glucose condition. B. The Western blotting results showed that compared with the mannitol control group and the LG group, the expression of LC3-Ⅱ was significantly reduced under high glucose condition. C. Quantitative statistics were conducted on Figure A, and the mean±standard deviation of each group was 0.26±0.19 for the mannitol group, 0.49±0.01 for the LG group, and 1.38±0.11 for the HG group. ①P=0.008, ②P=0.011. D. Quantitative statistics were performed on Figure B. The mean±standard deviation of each group was 1.02±0.17 for the mannitol group, 1.01±0.09 for the LG group, and 0.67±0.10 for the HG group. ③P=0.007, ④P=0.000。

Fig 5 High glucose-induced COMP overexpressed and inhibited autophagy

图6 敲低 COMP 水平促使足细胞mTOR表达降低和LC3-Ⅱ表达增加Note： A. The Western blotting results showed that in the cells infected with lentivirus, the expression of COMP was significantly reduced in the control group (control) and negative control group (NC), while the expression of p-mTOR was reduced and the expression of LC3-Ⅱ was significantly increased. B. The quantitative visualization view of COMP in Figure A shows that the mean±standard deviation of each group is 1.12±0.07 in the control group, 0.75±0.08 in the NC group, and 0.37±0.09 in the COMP RNAi (102289) group. ①P=0.000, ②P=0.004. C. The p-mTOR quantitative visualization view of Figure A shows mean±standard deviation for each group: 1.78±0.29 for the control group, 0.93±0.01 for the NC group, and 0.56±0.06 for the COMP RNAi (102289) group. ③P=0.005, ④P=0.018. D. The quantitative visualization view of LC3-Ⅱ in Figure A shows the mean±standard deviation of each group: 0.59±0.01 for the control group, 0.55±0.11 for the NC group, and 0.96±0.05 for the COMP RNAi (102289) group. ⑤P=0.007, ⑥P=0.003.

Fig 6 Knockdown of COMP levels reduced mTOR expression and increased LC3 expression in podocytes

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