Hu Miao, Deng Yi, Bai Yujie, Zhang Jiayan, Shen Xiahong, Shen Lei, Zhou Ling
Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.
J Inflamm Res. 2025 Jan 22;18:949-972. doi: 10.2147/JIR.S482047. eCollection 2025.
Renal failure related death caused by diabetic kidney disease (DKD) is an inevitable outcome for most patients. This study aimed to identify the critical genes involved in the onset and progression of DKD and to explore potential therapeutic targets of DKD.
We conducted a batch of protein quantitative trait loci (pQTL) Mendelian randomization analysis to obtain a group of proteins with causal relationships with DKD and then identified key proteins through colocalization analysis to determine correlations between variant proteins and disease outcomes. Subsequently, the specific mechanisms of key regulatory genes involved in disease progression were analyzed through transcriptome and single-cell analysis. Finally, we validated the mRNA expression of five key genes in the DKD mice model using reverse transcription quantitative PCR (RT-qPCR).
Five characteristic genes, known as protein kinase B beta (AKT2), interleukin-2 receptor beta (IL2RB), neurexin 3(NRXN3), slit homolog 3(SLIT3), and TATA box binding protein like protein 1 (TBPL1), demonstrated causal relationships with DKD. These key genes are associated with the infiltration of immune cells, and they are related to the regulatory genes associated with immunity. In addition, we also conducted gene enrichment analysis to explore the complex network of potential signaling pathways that may regulate these key genes. Finally, we identified the effectiveness and reliability of these selected key genes through RT-qPCR in the DKD mice model.
Our results indicated that the AKT2, IL2RB, NRXN3, SLIT3, and TBPL1 genes are closely related to DKD, which may be useful in the diagnosis and therapy of DKD.
糖尿病肾病（DKD）导致的肾衰竭相关死亡是大多数患者不可避免的结局。本研究旨在确定参与DKD发生和发展的关键基因，并探索DKD的潜在治疗靶点。
我们进行了一批蛋白质定量性状位点（pQTL）孟德尔随机化分析，以获得一组与DKD有因果关系的蛋白质，然后通过共定位分析鉴定关键蛋白质，以确定变异蛋白质与疾病结局之间的相关性。随后，通过转录组和单细胞分析，分析参与疾病进展的关键调控基因的具体机制。最后，我们使用逆转录定量PCR（RT-qPCR）在DKD小鼠模型中验证了五个关键基因的mRNA表达。
五个特征基因，即蛋白激酶Bβ（AKT2）、白细胞介素-2受体β（IL2RB）、神经纤连蛋白3（NRXN3）、缝隙同源物3（SLIT3）和类TATA盒结合蛋白1（TBPL1），与DKD存在因果关系。这些关键基因与免疫细胞浸润相关，并且它们与免疫相关的调控基因有关。此外，我们还进行了基因富集分析，以探索可能调节这些关键基因的潜在信号通路的复杂网络。最后，我们通过RT-qPCR在DKD小鼠模型中确定了这些选定关键基因的有效性和可靠性。
我们的结果表明，AKT2、IL2RB、NRXN3、SLIT3和TBPL1基因与DKD密切相关，这可能对DKD的诊断和治疗有用。
