Chronic Active Antibody-Mediated Rejection Is Associated With the Upregulation of Interstitial But Not Glomerular Transcripts

Abstract

Molecular assessment of renal allografts has already been suggested in antibody-mediated rejection (ABMR), but little is known about the gene transcript patterns in particular renal compartments. We used laser capture microdissection coupled with quantitative RT-PCR to distinguish the transcript patterns in the glomeruli and tubulointerstitium of kidney allografts in sensitized retransplant recipients at high risk of ABMR. The expressions of 13 genes were quantified in biopsies with acute active ABMR, chronic active ABMR, acute tubular necrosis (ATN), and normal findings. The transcripts were either compartment specific (TGFB1 in the glomeruli and HAVCR1 and IGHG1 in the tubulointerstitium), ABMR specific (GNLY), or follow-up specific (CXCL10 and CX3CR1). The transcriptional profiles of early acute ABMR shared similarities with ATN. The transcripts of CXCL10 and TGFB1 increased in the glomeruli in both acute ABMR and chronic active ABMR. Chronic active ABMR was associated with the upregulation of most genes (SH2D1B, CX3CR1, IGHG1, MS4A1, C5, CD46, and TGFB1) in the tubulointerstitium. In this study, we show distinct gene expression patterns in specific renal compartments reflecting cellular infiltration observed by conventional histology. In comparison with active ABMR, chronic active ABMR is associated with increased transcripts of tubulointerstitial origin.

Role of Complement System in Kidney Transplantation: Stepping From Animal Models to Clinical Application

“…Taken together, the increased intracellular cleavage of C3 and the activated CD46 signals result in elevated glycolysis and oxidative phosphorylation, which are essential for Th1 response and CTL activation. In accordance with these results, elevated expressions of the CD46 transcripts have been observed in the tubulointerstitial area of kidney allografts with chronic active antibody-mediated rejection (AMR), in which the Th1 response is required (114). A similar intracellular C5a-C5aR1 signaling also exists in T cells and could be amplified by CD46 signaling.…”

Immunoglobulin heavy constant gamma 1 silencing decreases tonicity‐responsive enhancer‐binding protein expression to alleviate diabetic nephropathy

“…The molecular assessment of gene transcript patterns, particularly renal compartments, has gained attention in recent years, but knowledge of the mechanisms by which they act still needs to be improved. Prior evidence indicates the involvement of IGHG1 upregulation in the tubulointerstitium with antibody‐mediated rejection of renal allografts 32 . Besides, increased IGHG1 was found in B cells of blood samples of active systemic lupus erythematosus 33 .…”

Applications of Transcriptomics in the Research of Antibody-Mediated Rejection in Kidney Transplantation: Progress and Perspectives

“…There are more than 20 cell types with distinct spatial organization in kidneys, 60 and the behaviors and gene expression in response to certain insults or pathological conditions, including ABMR, may differ between different compartments of the organ. 61 ScRNA-seq not only detects specific changes of a known cell type but also redefines kidney cell types based on the transcriptome patterns. 53 As a result, it can provide a new entry point for enhancing the knowledge of the immunological response behind the rejection and for developing the therapeutic strategy that has been limited by the complexity of the disease ( Figure 1 ).…”