Guizhou University Medical College, Guiyang, 550002, China.
Department of Anesthesiology, Guizhou Provincial People's Hospital, 83, Zhongshan Road, Nanming District, GuiyangGuizhou, 550002, China.
Sci Rep. 2024 Sep 27;14(1):22057. doi: 10.1038/s41598-024-72327-w.
Cognitive dysfunction caused by diabetes has become a serious global medical issue. Diabetic kidney disease (DKD) exacerbates cognitive dysfunction in patients, although the precise mechanism behind this remains unclear. Here, we conducted an investigation using RNA sequencing data from the Gene Expression Omnibus (GEO) database. We analyzed the differentially expressed genes in DKD and three types of neurons in the temporal cortex (TC) of diabetic patients with cognitive dysfunction. Through our analysis, we identified a total of 133 differentially expressed genes (DEGs) shared between DKD and TC neurons (62 up-regulated and 71 down-regulated). To identify potential common biomarkers, we employed machine learning algorithms (LASSO and SVM-RFE) and Venn diagram analysis. Ultimately, we identified 8 overlapping marker genes (ZNF564, VPS11, YPEL4, VWA5B1, A2ML1, KRT6A, SEC14L1P1, SH3RF1) as potential biomarkers, which exhibited high sensitivity and specificity in ROC curve analysis. Functional analysis using Gene Ontology (GO) revealed that these genes were primarily enriched in autophagy, ubiquitin/ubiquitin-like protein ligase activity, MAP-kinase scaffold activity, and syntaxin binding. Further enrichment analysis using Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) indicates that these biomarkers may play a crucial role in the development of cognitive dysfunction and diabetic nephropathy. Building upon these biomarkers, we developed a diagnostic model with a reliable predictive ability for DKD complicated by cognitive dysfunction. To validate the 8 biomarkers, we conducted RT-PCR analysis in the cortex, hippocampus and kidney of animal models. The results demonstrated the up-regulation of SH3RF1 in the cortex, hippocampus and kidney of mice, which was further confirmed by immunofluorescence and Western blot validation. Notably, SH3RF1 is a scaffold protein involved in cell survival in the JNK signaling pathway. Based on these findings, we support that SH3RF1 may be a common gene expression feature that influences DKD and cognitive dysfunction through the apoptotic pathway.
糖尿病引起的认知功能障碍已成为一个严重的全球医学问题。糖尿病肾病（DKD）可使伴有认知功能障碍的患者的认知功能恶化，但其确切机制尚不清楚。在这里，我们使用来自基因表达综合数据库（GEO）的 RNA 测序数据进行了一项研究。我们分析了 DKD 患者和伴有认知功能障碍的颞叶皮质（TC）三种神经元中差异表达的基因。通过分析，我们共鉴定出 DKD 和 TC 神经元之间的 133 个差异表达基因（DEGs）（62 个上调，71 个下调）。为了鉴定潜在的共同生物标志物，我们采用了机器学习算法（LASSO 和 SVM-RFE）和 Venn 图分析。最终，我们鉴定出 8 个重叠的标记基因（ZNF564、VPS11、YPEL4、VWA5B1、A2ML1、KRT6A、SEC14L1P1、SH3RF1）作为潜在的生物标志物，在 ROC 曲线分析中具有较高的灵敏度和特异性。使用基因本体论（GO）进行的功能分析表明，这些基因主要富集在自噬、泛素/泛素样蛋白连接酶活性、MAP-激酶支架活性和突触素结合中。使用基因集富集分析（GSEA）和基因集变异分析（GSVA）进一步富集分析表明，这些生物标志物可能在认知功能障碍和糖尿病肾病的发生发展中发挥关键作用。基于这些生物标志物，我们建立了一个对并发认知功能障碍的 DKD 具有可靠预测能力的诊断模型。为了验证这 8 个生物标志物，我们在动物模型的大脑皮层、海马体和肾脏中进行了 RT-PCR 分析。结果表明，在小鼠的大脑皮层、海马体和肾脏中，SH3RF1 表达上调，免疫荧光和 Western blot 验证进一步证实了这一点。值得注意的是，SH3RF1 是一种参与 JNK 信号通路中细胞存活的支架蛋白。基于这些发现，我们支持 SH3RF1 可能是一种共同的基因表达特征，通过凋亡途径影响 DKD 和认知功能障碍。
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