Antibody-mediated rejection (AMR) has been identified as a main obstacle for stable immune tolerance and long survival of kidney allografts. In spite of new insights into the underlying mechanisms of AMR, accurate diagnosis and efficient treatment are still challenges in clinical practice. Endothelium is the first barrier between recipients’ immune systems and grafts in vascularized organ transplants. Considering that endothelial cells express a number of antigens that can be attacked by various allo- and autoantibodies, endothelial cells act as main targets for the recipients’ humoral immune responses. Importantly, emerging evidence has shown that endothelial cells in transplants could also initiate protective mechanisms in response to immune injuries. A better understanding of the role of endothelial cells during the pathogenesis of AMR might provide novel therapeutic targets. In the present review, we summarize the antigens expressed by endothelial cells and also discuss the activation and accommodation of endothelial cells as well as their clinical implications. Collectively, the progress discussed in this review indicates endothelial cells as promising targets to improve current diagnosis and therapeutic regimens for AMR.

Acute renal allograft rejection is a common complication after renal transplantation that often leads to chronic rejection and ultimate graft loss. While renal allograft biopsy remains the gold standard for diagnosis of acute rejection, the possibility of biopsy-associated complications cannot be overlooked. The development of noninvasive methods for accurate detection of acute renal allograft rejection is thus of significant clinical importance. Gas chromatography–mass spectrometry (GC/MS) was employed for analysis of urine metabolites in 15 renal allograft recipients with acute rejection and 15 stable renal transplant recipients. Partial least squares (PLS) regression and leave-one-out analyses were performed to ascertain whether the metabolites identified could be exploited to distinguish acute rejection from stable groups as well as their sensitivity and specificity. Overall, 14 metabolites were significantly altered in the acute rejection group (11 and 3 metabolites displayed higher and lower levels, respectively) relative to the stable transplant group. Data from PLS and leave-one-out analyses revealed that the differential metabolites identified not only distinguished acute rejection from stable transplant recipients but also showed high sensitivity and specificity for diagnosis of renal allograft recipients with acute rejection. Urine metabolites identified with GC/MS can effectively distinguish acute rejection from stable transplant recipients, supporting the potential utility of metabolome analysis in non-invasive diagnosis of acute rejection.

Acetaminophen (APAP) overdose is a known cause of acute kidney injury, yet the underlying molecular mechanisms remain incompletely understood. In this study, we conducted integrated transcriptomic, proteomic, and phosphoproteomic analyses of kidney tissues from mice with early-stage APAP-induced nephrotoxicity and corresponding controls. A total of 884 genes related to 13 distinct forms of programmed cell death (PCD)-including alkaliptosis, apoptosis, autophagy, cuproptosis, disulfidptosis, entotic cell death, ferroptosis, lysosome-dependent cell death, necroptosis, netotic cell death, oxeiptosis, parthanatos, and pyroptosis-were systematically evaluated. Gene set variation analysis was employed to assess the activity of these pathways in APAP-injured kidneys. Moreover, phosphokinase profiling and in vivo inhibition of protein kinase B (AKT) and extracellular signal-regulated kinase were performed to identify potential therapeutic strategies. Pathway enrichment across transcriptomic and proteomic datasets consistently pointed to drug metabolism-particularly cytochrome P450-as a central player. Transcriptomic profiling highlighted six PCD pathways-alkaliptosis, cuproptosis, disulfidptosis, lysosome-dependent cell death, netotic cell death, and pyroptosis-as notably activated in response to APAP exposure. Proteomic analysis further revealed enrichment of eight PCD pathways, including alkaliptosis, apoptosis, entotic cell death, ferroptosis, necroptosis, netotic cell death, oxeiptosis, and pyroptosis. Therapeutically, in vivo inhibition of AKT significantly alleviated renal injury, as demonstrated by improved histopathology, reduced neutrophil gelatinase-associated lipocalin and blood urea nitrogen and suppression of ferroptosis mediators TFRC and ACSL4. Concurrently, it enhanced phosphorylation of p70S6K and FOXO, reflecting improved survival signaling and reduced apoptosis. Together, these findings demonstrate that multiple PCD pathways contribute to early APAP-induced nephrotoxicity and nominate AKT as a central regulatory hub, which merits further exploration in translational nephrotoxicity research.

Antibody-mediated rejection (AMR) represents a major cause of allograft dysfunction and results in allograft failure in solid organ transplantation. Cyclic helix B peptide (CHBP) is a novel erythropoietin-derived peptide that ameliorated renal allograft rejection in a renal transplantation model. However, its effect on AMR remains unknown. This study aimed to investigate the effect of CHBP on AMR using a secondary allogeneic skin transplantation model, which was created by transplanting skin from BALB/c mice to C57BL/6 mice with or without CHBP treatment. A secondary syngeneic skin transplantation model, involving transplantation from C57BL/6 mice to C57BL/6 mice, was also created to act as a control. Skin graft rejection, CD19⁺ B cell infiltration in the skin allograft, the percentages of splenic plasma cells, germinal center (GC) B cells, and Tfh cells, the serum levels of donor specific antibodies (DSAs), and NF-κB signaling in splenocytes were analyzed. Skin allograft survival was significantly prolonged in the CHBP group compared to the allogeneic group. CHBP treatment also significantly reduced the CD19⁺ B cell infiltration in the skin allograft, decreased the percentages of splenic plasma cells, GC B cells, and Tfh cells, and ameliorated the increase in the serum DSA level. At a molecular level, CHBP downregulated P100, RelB, and P52 in splenocytes. CHBP prolonged skin allograft survival by inhibiting AMR, which may be mediated by inhibition of NF-κB signaling to suppress B cell immune responses, thereby decreasing the DSA level.

Mesenchymal stem cells (MSCs) are the hotspots of cellular therapy due to their low immunogenicity, potent immunoregulation, and unique renoprotection. The present study aimed to investigate the effects of periosteum-derived MSCs (PMSCs) in ischemia–reperfusion (IR)-mediated renal fibrosis. Using cell proliferation assay, flow cytometry, immunofluorescence, and histologic analysis, the differences in cell characteristics, immunoregulation, and renoprotection of PMSCs were compared to the bone marrow-derived MSCs (BMSCs), the most frequently studied stem cells in cellular therapy. In addition, the mechanism of PMSC renoprotection was investigated by 5′ end of the RNA transcript sequencing (SMART-seq) and mTOR knockout mice. The proliferation and differentiation capabilities of PMSCs were stronger than those of BMSCs. Compared with BMSCs, the PMSCs exerted a better effect on alleviating renal fibrosis. Meanwhile, the PMSCs more effectively promote Treg differentiation. Treg exhaustion experiment indicated that Tregs exerted an important effect on inhibiting renal inflammation and acted as a critical mediator in PMSC renoprotection. Additionally, SMART-seq results implied that the PMSCs promoted Treg differentiation, possibly via the mTOR pathway. In vivo and in vitro experiments showed that PMSC inhibited mTOR phosphorylation of Treg. After mTOR knockout, the PMSCs failed to promote Treg differentiation. Compared with BMSCs, the PMSCs exerted stronger immunoregulation and renoprotection that was mainly attributed to PMSC promotion for Treg differentiation by inhibiting the mTOR pathway.

[This corrects the article DOI: 10.1155/2017/8746303.].