基于生物信息学分析研究环境污染物对糖尿病肾病的影响及其分子机制

Bioinformatics analysis of effects and molecular mechanism of environmental pollutants on diabetic nephropathy

环境污染物是包括重金属、持久性有机污染物等在内一系列物质的总称,其可通过各种途径影响代谢类疾病及并发症的发生发展.糖尿病肾病(DN)作为糖尿病最严重的微血管并发症之一,现已成为我国终末期肾病的主要病因.本研究旨在探讨可作用于DN疾病变化进程的环境污染物及其调控机制,从而为糖尿病及DN患者精准预防和临床治疗提供一定理论依据.通过Gene Expression Omnibus(GEO)和Comparative Toxicogenomics Database(CTD)数据库获取环境污染物影响DN的相关基因,其中经GEO数据库挖掘得到9个与DN相关联的数据集,标准化后筛选去重得到差异基因1326个,CTD数据库获得环境污染物影响DN的相关基因19557个,二者取交集得到共同基因1176个,利用DAVID数据库进行GO和KEGG富集分析,再将共同基因导入String数据库和Cytoscape软件获取关键基因,利用Metascape在线平台进行Mcode模块化分析,分析得出内分泌干扰物雌二醇、双酚A是影响DN的主要环境污染物,分子对接表明主要环境污染物与关键基因翻译后的蛋白结构结合活性良好,且主要通过LEU、LYS等氨基酸残基位点直接作用于关键基因蛋白.最后,利用GEPIA在线平台验证Top20关键基因在肾透明细胞癌(KIRC)样本中的表达,并进行了Kaplan-Meier生存分析,其中8个显著表达基因与KIRC患者预后关系紧密,进一步探讨了环境污染物暴露介导的DN与肾癌关系.综上,环境污染物可通过以中性粒细胞为核心的炎症反应诱发和促进DN,在影响DN病理生理进程的同时还对其合并肾癌存在诱发效应.

Environmental pollutants include heavy metals,persistent organic pollutants and so on,which can affect the occurrence and development of metabolic diseases and complications through various ways.Diabetic nephropathy(DN)is one of the most serious microvascular complications of diabetes,which has become the main cause of end-stage renal disease in China.This study aim to explore the environmental pollutants which play important role on the process of DN disease and its regulatory mechanisms its regulatory mechanisms,thus providing theoretical basis for the precise prevention and future clinical treatment of diabetes and DN patients.The related genes of environmental pollutants affecting DN were obtained through Gene Expression Omnibus(GEO)and Comparative Toxicogenomics Database(CTD)databases.Then,9 datasets associated with DN were obtained from the GEO database.After standardization,1326 differential genes were obtained by screening and deduplication.19557 genes related to environmental pollutants affecting DN were obtained from the CTD database,and 1176 common genes were obtained between GEO and CTD database.Next,GO and KEGG enrichment analyses were conducted through DAVID database,and then the common genes were imported into String database and Cytoscope software to obtain key genes.Mcode modular analysis were performed using the Metascape online platform.The analysis showed that the endocrine disruptors estradiol and bisphenol A were the main environmental pollutants affecting DN.Molecular docking showed that the main environmental pollutants had strong binding activity with proteins structure of key genes,and they mainly acted directly through amino acid residues such as LEU and LYS.Finally,the expression of these Top20 key genes in kidney renal clear cell carcinoma(KIRC)sample was further verified using GEPIA online platform and Kaplan-Meier survival curves were constructed.The results showed that 7 significantly expressed genes were closely related to the prognosis of KIRC patients,and further explored the relationship between DN and renal cancer mediated by environmental pollutants exposure.In conclusion,environmental pollutants can induce and promote DN through the inflammatory response and neutrophils play an extremely important role in these process.Further,it also has an inducing effect on its concomitant kidney cancer while affecting the pathophysiological process of DN.