Identifying the molecular mechanisms of sepsis-associated acute kidney injury and predicting potential drugs

by Selleckchem | Jun 11 2023

Objective: To provide insights into the diagnosis and therapy of SA-AKI via ferroptosis genes.

Methods: Based on three datasets (GSE57065, GSE30718, and GSE53771), we used weighted co-expression network analysis to identify the key regulators of SA-AKI, its potential biological functions, and constructed miRNA‒mRNA complex regulatory relationships. We also performed machine learning and in vitro cell experiments to identify ferroptosis genes that are significantly related to SA-AKI in the two datasets. The CIBERSORT algorithm evaluates the degree of infiltration of 22 types of immune cell. We compared the correlation between ferroptosis and immune cells by Pearson's correlation analysis and verified the key genes related to the immune response to reveal potential diagnostic markers. Finally, we predicted the effects of drugs and the potential therapeutic targets for septic kidney injury by pRRophetic.

Results: We found 264 coDEGs involving 1800 miRNA molecules that corresponded to 210 coDEGs. The miRNA‒mRNA ceRNA interaction network was constructed to obtain the top-10 hub nodes. We obtained the top-20 ferroptosis genes, 11 of which were in the intersection. We also identified a relationship between ferroptosis genes and the immune cells in the AKI dataset, which showed that neutrophils were activated and that regulatory T cells were surpassed. Finally, we identified EHT1864 and salubrinal as potential therapeutic agents.

Conclusion: This study demonstrated the roles of miR-650 and miR-296-3p genes in SA-AKI. Furthermore, we identified OLFM4, CLU, RRM2, SLC2A3, CCL5, ADAMTS1, and EPHX2 as potential biomarkers. The irregular immune response mediated by neutrophils and Treg cells is involved in the development of AKI and shows a correlation with ferroptosis genes. EHT 1864 and salubrinal have potential as drug candidates in patients with septic acute kidney injury.

Comments:

The study aimed to investigate the diagnosis and therapy of septic acute kidney injury (SA-AKI) by focusing on ferroptosis genes. Here are the key findings and steps followed:

Dataset and Analysis: That utilized three datasets (GSE57065, GSE30718, and GSE53771) and performed weighted co-expression network analysis to identify key regulators of SA-AKI and their biological functions. That constructed miRNA‒mRNA complex regulatory relationships.

Immune Cell Infiltration: That employed the CIBERSORT algorithm to evaluate the degree of infiltration of 22 types of immune cells. By comparing the correlation between ferroptosis and immune cells using Pearson's correlation analysis, you revealed the relationship between ferroptosis genes and immune cells, highlighting the activation of neutrophils and the predominance of regulatory T cells (Tregs) in the AKI dataset.

Therapeutic Targets and Drugs: By utilizing the pRRophetic tool, you predicted the effects of drugs and potential therapeutic targets for septic kidney injury. EHT1864 and salubrinal were identified as potential therapeutic agents for SA-AKI.

In conclusion, the study highlighted the roles of miR-650 and miR-296-3p genes in SA-AKI and identified potential biomarkers such as OLFM4, CLU, RRM2, SLC2A3, CCL5, ADAMTS1, and EPHX2. The study also revealed the correlation between ferroptosis genes and immune cells, with activated neutrophils and an imbalance of Treg cells playing a role in AKI development. Lastly, EHT 1864 and salubrinal were proposed as potential drug candidates for patients with septic acute kidney injury.