Abstract
BackgroundIschemia–reperfusion injury (IRI) remains an inevitable and major challenge in renal transplantation. The current study aims to obtain deep insights into underlying mechanisms and seek prognostic genes as potential therapeutic targets for renal IRI (RIRI).MethodsAfter systematically screening the Gene Expression Omnibus (GEO) database, we collected gene expression profiles of over 1,000 specimens from 11 independent cohorts. Differentially expressed genes (DEGs) were identified by comparing allograft kidney biopsies taken before and after reperfusion in the discovery cohort and further validated in another two independent transplant cohorts. Then, graft survival analysis and immune cell analysis of DEGs were performed in another independent renal transplant cohort with long-term follow-ups to further screen out prognostic genes. Cell type and time course analyses were performed for investigating the expression pattern of prognostic genes in more dimensions utilizing a mouse RIRI model. Finally, two novel genes firstly identified in RIRI were verified in the mouse model and comprehensively analyzed to investigate potential mechanisms.ResultsTwenty DEGs upregulated in the process of RIRI throughout different donor types (living donors, cardiac and brain death donors) were successfully identified and validated. Among them, upregulation of 10 genes was associated with poor long-term allograft outcomes and exhibited strong correlations with prognostic immune cells, like macrophages. Furthermore, certain genes were found to be only differentially expressed in specific cell types and remained with high expression levels even months after RIRI in the mouse model, which processed the potential to serve as therapeutic targets. Importantly, two newly identified genes in RIRI, Btg2 and Rhob, were successfully confirmed in the mouse model and found to have strong connections with NF-κB signaling.ConclusionsWe successfully identified and validated 10 IRI-associated prognostic genes in renal transplantation across different donor types, and two novel genes with crucial roles in RIRI were recognized for the first time. Our findings offered promising potential therapeutic targets for RIRI in renal transplantation.
Highlights
Ischemia–reperfusion injury (IRI), a major and inevitable complication that occurred during organ transplantation, involves an initial restriction of blood supply followed by the subsequent restoration of perfusion [1]
Differential expression analyses were performed in biopsies taken before and after reperfusion from living and deceased donor kidneys (DBD and donation after cardiac death (DCD)) to select robust and general genes
Results showed that 20 genes were all strongly connected without exception
Summary
Ischemia–reperfusion injury (IRI), a major and inevitable complication that occurred during organ transplantation, involves an initial restriction of blood supply followed by the subsequent restoration of perfusion [1]. Current experimental strategies to prevent or alleviate RIRI can be focused on scavenging ROS, reducing inflammation, or promoting cell survival and regeneration, including cellular therapy, pharmacological treatment, and ischemic preconditioning [9,10,11,12] Despite those methods, there is still a lack of effective treatment in clinical settings [13]. With the expansion of donor pools in recent years, donation after brain death (DBD) and donation after cardiac death (DCD) have been gradually increased These deceased allografts experienced more severe IRI and were at higher risk of graft loss [14, 15]. The current study aims to obtain deep insights into underlying mechanisms and seek prognostic genes as potential therapeutic targets for renal IRI (RIRI)
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