Integrated Analysis of Prognostic Genes Associated With Ischemia-Reperfusion Injury in Renal Transplantation.
Integrated Analysis of Prognostic Genes Associated With Ischemia-Reperfusion Injury in Renal Transplantation.
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DOI：
10.3389/fimmu.2021.747020
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发表时间：
2021
影响因子：
7.3
通讯作者：
Hu X
中科院分区：
文献类型：
--
作者：
Zhang D;Wang Y;Zeng S;Zhang M;Zhang X;Wang Y;Zhang Z;Wang X;Hu X
缺血再灌注损伤（IRI）仍然是肾移植中不可避免的主要挑战。目前的研究旨在深入了解潜在机制并寻找预后基因作为肾 IRI (RIRI) 的潜在治疗靶点。在系统筛选基因表达综合 (GEO) 数据库后，我们收集了来自 11 个独立队列的 1,000 多个样本的基因表达谱。通过比较发现队列再灌注之前和之后进行的同种异体移植肾活检来鉴定差异表达基因（DEG），并在另外两个独立移植队列中进一步验证。然后，在另一个独立的肾移植队列中进行移植物存活分析和DEGs免疫细胞分析并进行长期随访，以进一步筛选预后基因。利用小鼠 RIRI 模型进行细胞类型和时间过程分析，以在更多维度上研究预后基因的表达模式。最后，在小鼠模型中验证了 RIRI 中首次发现的两个新基因，并进行了全面分析以研究潜在机制。成功鉴定和验证了不同供体类型（活体供体、心脏和脑死亡供体）的 RIRI 过程中上调的 20 个 DEG。其中，10 个基因的上调与长期同种异体移植结果不佳相关，并与巨噬细胞等预后免疫细胞具有很强的相关性。此外，发现某些基因仅在特定细胞类型中差异表达，并且在小鼠模型中即使在 RIRI 数月后仍保持高表达水平，这具有作为治疗靶点的潜力。重要的是，RIRI 中新发现的两个基因 Btg2 和 Rhob 在小鼠模型中得到了成功证实，并发现它们与 NF-κB 信号传导密切相关。我们在不同供体类型的肾移植中成功鉴定并验证了 10 个与 IRI 相关的预后基因，其中两个在 RIRI 中具有关键作用的新基因首次被识别。我们的研究结果为肾移植中的 RIRI 提供了有希望的潜在治疗靶点。
Ischemia–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). After 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. Twenty 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. We 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.
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