Decoding the interplay between COVID-19 and diabetic nephropathy through bioinformatics and systems biology techniques

Individuals with diabetic nephropathy (DN), a major diabetic complication, have been disproportionately affected by the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to investigate the molecular interplay between COVID-19 and DN using bioinformatics and systems biology approaches to identify shared mechanisms and therapeutic targets for their improved synergistic clinical management.

Transcriptomic datasets (COVID-19, GSE171110; DN, GSE30528) were analyzed to identify differentially expressed genes (DEGs). Additionally, functional enrichment, protein-protein interaction (PPI) networks, transcription factor (TF)-microRNA (miRNA) regulatory networks, and drug-gene associations were explored. The diagnostic potential of hub genes was validated using receiver operating characteristic curves.

In total, 3975 DEGs (2796 upregulated; 1179 downregulated) were identified in patients with COVID-19 versus controls, and 348 DEGs (93 upregulated; 255 downregulated) were found in patients with DN. Among them, 83 DEGs overlapped, presenting shared molecular pathways, including hematopoietic cell lineage, focal adhesion, and complement/coagulation cascades. PPI analysis revealed five major hub genes (IL7R, CD2, GZMA, CD3D, and FCER1A) associated with immune regulation and tissue injury, and regulatory network analysis identified 46 TFs and 88 miRNAs interacting with them. Based on transcriptomic signatures, drug repurposing candidates, such as alpha-d-mannose, aspirin, and methotrexate, were identified. Additionally, hub genes showed a high diagnostic potential (area under the curve >0.80 for COVID-19 and DN). Finally, we use external datasets to validate hub genes.

The findings of this study reveal shared molecular pathways and hub genes between COVID-19 and DN, providing insights into immune dysregulation and tissue injury mechanisms. Strategies associated with identified biomarkers and therapeutic candidates, including interleukin-7 receptor-targeting strategies, offer the potential for improving clinical outcomes in patients with comorbid COVID-19 and DN. Lastly, these findings underscore the value of integrative bioinformatics in guiding precision medicine approaches for complex disease interactions.