Integrated Analysis of Prognostic Genes Associated With Ischemia–Reperfusion Injury in Renal Transplantation

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.

Differential role for rapid proteostasis in Rho GTPase-mediated control of quiescent endothelial integrity

“…Besides, high RhoB expression was detected in intestinal, inflamed blood vessels of patients with Crohn’s disease ( 47 ). Elevated RhoB levels have also been found in urine of patients with chronic kidney disease, and RhoB has been identified as an upregulated gene 2 to 24 h after renal ischemia-reperfusion injury following kidney transplantation ( 49 , 50 ). However, once activated, RhoA and RhoB share overlapping downstream signaling, comprising activation of ROCK and the induction of actomyosin-based contraction ( Fig.…”

Rapid proteostasis controls monolayer integrity of quiescent endothelium

“…Besides, high RhoB expression was detected in intestinal, inflamed blood vessels of patients with Crohn’s disease (Marcos-Ramiro et al 2016). Elevated RhoB levels have also been found in urine of patients with chronic kidney disease and RhoB has been identified as upregulated gene 2 - 24h after renal ischemia-reperfusion injury after kidney transplantation (Konvalinka et al 2016; Zhang et al 2021). However, once activated, RhoA and RhoB share overlapping downstream signaling, comprising activation of ROCK and the induction of actomyosin-based contraction (Figure 6C).…”

Soluble Programmed Cell Death Protein 1 and Its Ligand: Potential Biomarkers to Predict Acute Kidney Injury After Surgery in Critically Ill Patients

“…Tubular necrosis in the outer medulla region of the kidney was observed under × 200 magnification, assessed by hematoxylin and eosin (HE) staining, as reported before. 21–23 The left kidney of the mouse was fixed with 10% paraformaldehyde solution. Renal tissue specimen was embedded with paraffin wax and sliced for HE staining.…”