糖尿病肾脏疾病肾小管铁死亡关键特异性基因的研究初探  

Preliminary study of key specific genes involved in tubular ferroptosis in diabetic kidney disease

作　　者：马莉莉[1] 蒋麟 付丽[1] 魏蕊 王婷婷[1] Ma Li-li;J iang Lin;Fu Li;Wei Rui;Wang Ting-ting(IInternational Medical Center,Beijing Friendship Hospital,Capital Medical University,Beijing 100050,China;Department of General Surgery,the Fifth Clinical Center(South District),Chinese PLA General Hospital,Beijing 100071,China)

机构地区：[1]首都医科大学附属北京友谊医院国际医疗中心,北京100050 [2]中国人民解放军总医院第五临床中心(南区)普通外科,北京100071

出　　处：《临床肾脏病杂志》2025年第2期143-151,共9页Journal Of Clinical Nephrology

基　　金：北京市自然科学基金项目(7232036、7232030)。

摘　　要：目的 通过生物信息学分析方法探讨糖尿病肾脏疾病(diabetic kidney disease,DKD)肾小管间质铁死亡的特异性关键基因及其临床意义。方法 下载DKD、非DKD患者肾间质组织数据集,筛选差异表达基因(differential expression analysis, DEG),识别DKD特异性铁死亡相关基因,并进行功能富集和蛋白质相互作用网络(protein-protein interaction, PPI)分析,筛选出关键基因后进行临床相关性分析和实时定量聚合酶链式反应(quantitative real-time PCR, qPCR)验证,并分析关键基因及免疫微环境关系。结果 本研究筛选出37个与铁死亡相关的DEGs。这些基因主要参与代谢、脂质过氧化和炎症反应信号通路。37个铁死亡相关基因中有5个基因(PTEN、VEGFA、HSPA5、MAPK8、CD44、ATM)被鉴定为特异性DKD铁死亡基因。qPCR显示高糖处理的人肾皮质近曲肾小管(human kidney-2,HK-2)细胞中,PTEN mRNA水平显著上调,而VEGFA mRNA水平显著下调。Nephroseq数据显示,VEGFA的mRNA表达水平与肾小球滤过率(glomerular filtration rate, GFR)呈正相关,Person相关系数为0.67(P<0.05),与24 h尿蛋白定量及血肌酐负相关,r值为-0.79(P<0.05)。HSPA5、PTEN的mRNA表达水平与DKD患者GFR呈负相关,r值分别为-0.60和-0.90(P<0.05),ATM的mRNA表达水平与血肌酐呈正相关,r值为0.53(P<0.05)。VEGFA mRNA表达水平与记忆T细胞呈正相关,r值为0.69(P<0.05)。结论 VEGFA和PTEN可能为参与DKD铁死亡的特异性关键分子,可能通过脂质代谢、氧化应激和炎症反应等机制参与DKD的发生发展。Objective To explore the key genes of ferroptosis involved in renal tubulointerstitium of diabetic kidney disease(DKD)and its clinical relevance by bioinformatics analysis.Methods DKD and non-DKD datasets of renal tubulointerstitial tissue were obtained to identify differentially expressed genes(DEGs),and DKD-specific ferroptosis-related genes.Functional enrichment and proteinprotein interaction network(PPI)analyses were conducted.After screening key genes,clinical correlation analysis and quantitative real-time PCR(qPCR)were performed for validation.The relationship between key genes and immune microenvironment was explored.Results A total of 37 ferroptosisassociated DEGs in DKD were screened,and they were mainly enriched in metabolic,lipid peroxidation,and inflammatory response signaling pathways.Among the 37 ferroptosis-related genes,5 genes (PTEN, VEGFA, HSPA5, MAPK8, CD44, ATM) were identified as DKD-specific ferroptosis-associated genes. qPCR showed that the mRNA level of PTEN was significantly up-regulated and that of VEGFA was significantly down-regulated in high glucose-treated human kidney proximal tubular epi thelial (HK-2) cells. Nephroseq data showed that the mRNA expression level of VEGFA was positively correlated with glomerular filtration rate (GFR), and the Person correlation coefficient (r value) was 0. 67 (P<0. 05). It was negatively correlated with urinary protein and serum creatinine, with the r value of -0. 79 (P<0. 05). The mRNA levels of HSPA5 and PTEN were negatively correlated with GFR in DKD patients, with r values of -0. 60 and -0. 90, respectively (P<0. 05). The mRNA level of ATM was positively correlated with serum creatinine, with the r value of 0. 53 (P<0. 05). The mRNA level of VEGFA was positively correlated with memory T cells, with the r value of 0. 69 (P<0. 05). Conclusions VEGFA and PTEN may be specific molecules involved in ferroptosis in DKD, and may participate in the occurrence and development of DKD via regulating lipid metabolism, oxidative stress, and inflammatory resp

关 键 词：糖尿病肾脏疾病 铁死亡 炎症反应 

分 类 号：R58[医药卫生—内分泌]