Exploration of the shared gene signatures and biological mechanisms between ischemia-reperfusion injury and antibody-mediated rejection in renal transplantation.

BACKGROUND

Antibody-mediated rejection (ABMR) plays a crucial role in graft loss during allogeneic renal transplantation. In renal transplantation, ischemia-reperfusion injury (IRI) is unavoidable, serves as a major contributor to acute rejection, and is linked to graft loss. However, the mechanisms underlying IRI and ABMR are unclear. Therefore, this study aimed to investigate the shared genetic characteristics and biological mechanisms between IRI and ABMR.

METHODS

Gene expressions for IRI (GSE43974) and ABMR (GSE129166 and GSE36059) were retrieved from the Gene Expression Omnibus database. The shared differentially expressed genes (DEGs) of IRI and ABMR were identified, and subsequent functional enrichment analysis was performed. Immune cell infiltration in ABMR and its relationship with the shared DEGs were investigated using the CIBERSORT method. Random forest analysis, a protein-protein interaction network, and Cytoscape were used to screen hub genes, which were subsequently subjected to gene set enrichment analysis, miRNA prediction, and transcription factors analysis. The survival analysis was performed through Kaplan-Meier curves. Finally, drug compound prediction was performed on the shared DEGs using the Drug Signature Database.

RESULTS

Overall, 27 shared DEGs were identified between the renal IRI and ABMR groups. Among these, 24 genes exhibited increased co-expression, whereas none showed decreased co-expression. The shared DEGs were primarily enriched in the inflammation signaling pathways. Notably, CD4 memory T cells were identified as potential critical mediators of IRI, leading to ABMR. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3), interferon regulatory factor 1 (IRF1), and early growth response 2 (EGR2) were identified as key components in the potential mechanism that link IRI and ABMR. Patients undergoing renal transplantation with higher expression levels of TNFAIP3, IRF1, and EGR2 exhibited decreased survival rates compared to those with lower expression levels.

CONCLUSION

Inflammation is a key mechanism that links IRI and ABMR, with a potential role played by CD4 memory T cells. Furthermore, TNFAIP3, IRF1, and EGR2 are implicated in the underlying mechanism between IRI and ABMR.