基于加权基因共表达网络分析（WGCNA）和机器学习算法鉴定醛脱氢酶2（ALDH2）作为肾移植急性肾损伤治疗的新靶点，并通过动物实验探索其潜在作用机制。
Identification of ALDH2 as a novel target for the treatment of acute kidney injury in kidney transplantation based on WGCNA and machine learning algorithms and exploration of its potential mechanism of action using animal experiments.
作者信息
Peng Jinpu, Wang Shili, Pan Xingyu, Wu Moudong, Zhan Xiong, Wang Dan, Zhu Guohua, Wang Wei, Tang Hongyu, An Nini, Pei Jun
机构信息
Department of Pediatric Surgrey, Guizhou Provincial People's Hospital, Guiyang, China.
出版信息
Front Immunol. 2025 Mar 4;16:1536800. doi: 10.3389/fimmu.2025.1536800. eCollection 2025.
BACKGROUND
Acute kidney injury (AKI) after kidney transplantation is one of the main causes of graft loss and poor patient prognosis, and it is important to explore new targets for treating AKI in kidney transplantation.
METHODS
Based on the kidney transplantation AKI-related dataset GSE30718, the most relevant modular genes for AKI among them were firstly screened using WGCNA and intersected with the DEGs, and the intersected genes were used as candidate genes for kidney transplantation AKI. Second, machine learning algorithms were utilized to identify the key genes among them, and the HPA database was used to explore the expression landscape. Next, we constructed a rat renal IRI model and explored the role of key genes in renal IRI. Finally, we combined ssGSEA enrichment analysis with animal experiments to further validate the potential mechanism of action of key genes.
RESULTS
In total, we identified 98 of the most relevant modular genes for AKI and 417 DEGs, which intersected to yield a total of 24 AKI candidate genes. Next, we intersected the key genes identified by three types of machine learning, namely, Random Forest, LASSO regression analysis and SVM, and obtained a total of 1 intersected gene as ALDH2, which we used as a key gene in kidney transplantation AKI. Using the HPA database, we found that ALDH2 has a high expression level in renal tissues and is mainly located in renal tubular epithelial cells. Next, we found in a rat renal IRI model that increasing the expression of ALDH2 alleviated the impairment of renal function and decreased the expression of NGAL, a marker of tubular injury, and BAX, an apoptotic protein, as well as reducing the expression of the inflammatory factors IL1β and IL6. Finally, using ssGSEA enrichment analysis and animal experiments, we further found that ALDH2 was able to inhibit the activation of the MAPK signaling pathway.
CONCLUSION
ALDH2 may serve as a novel target for the treatment of kidney transplantation AKI, and increasing the expression level of ALDH2 has a protective effect on renal IRI, and this protective effect may be achieved by inhibiting the MAPK signaling pathway.
背景
肾移植术后急性肾损伤（AKI）是移植物丢失和患者预后不良的主要原因之一，探索肾移植中治疗AKI的新靶点具有重要意义。
方法
基于肾移植AKI相关数据集GSE30718，首先利用WGCNA筛选其中与AKI最相关的模块基因，并与差异表达基因（DEGs）进行交集分析，将交集基因作为肾移植AKI的候选基因。其次，利用机器学习算法鉴定其中的关键基因，并使用人类蛋白质图谱（HPA）数据库探索其表达格局。接下来，构建大鼠肾缺血再灌注损伤（IRI）模型，探讨关键基因在肾IRI中的作用。最后，将单样本基因集富集分析（ssGSEA）与动物实验相结合，进一步验证关键基因的潜在作用机制。
结果
我们总共鉴定出98个与AKI最相关的模块基因和417个DEGs，二者交集后共产生24个AKI候选基因。接下来，我们将随机森林、LASSO回归分析和支持向量机（SVM）这三种机器学习方法鉴定出的关键基因进行交集分析，共获得1个交集基因醛脱氢酶2（ALDH2），我们将其作为肾移植AKI的关键基因。利用HPA数据库，我们发现ALDH2在肾组织中具有高表达水平，且主要定位于肾小管上皮细胞。接下来，我们在大鼠肾IRI模型中发现，增加ALDH2的表达可减轻肾功能损害，降低肾小管损伤标志物中性粒细胞明胶酶相关脂质运载蛋白（NGAL）和凋亡蛋白BAX的表达，并减少炎症因子白细胞介素1β（IL1β）和白细胞介素6（IL6）的表达。最后，通过ssGSEA和动物实验，我们进一步发现ALDH2能够抑制丝裂原活化蛋白激酶（MAPK）信号通路的激活。
结论
ALDH2可能是治疗肾移植AKI的新靶点，提高ALDH2的表达水平对肾IRI具有保护作用，且这种保护作用可能是通过抑制MAPK信号通路实现的。
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