Integrative Omics Analysis Unravels Microvascular Inflammation-Related Pathways in Kidney Allograft Biopsies

Abstract

In solid-organ transplantation, microRNAs (miRNAs) have emerged as key players in the regulation of allograft cells function in response to injury. To gain insight into the role of miRNAs in antibody-mediated rejection, a rejection phenotype histologically defined by microvascular inflammation, kidney allograft biopsies were subjected to miRNA but also messenger RNA (mRNA) profiling. Using a unique multistep selection process specific to the BIOMARGIN study (discovery cohort, N=86; selection cohort, N=99; validation cohort, N=298), six differentially expressed miRNAs were consistently identified: miR-139-5p (down) and miR-142-3p/150-5p/155-5p/222-3p/223-3p (up). Their expression level gradually correlated with microvascular inflammation intensity. The cell specificity of miRNAs target genes was investigated by integrating their in vivo mRNA targets with single-cell RNA sequencing from an independent allograft biopsy cohort. Endothelial-derived miR-139-5p expression correlated negatively with MHC-related genes expression. Conversely, epithelial-derived miR-222-3p overexpression was strongly associated with degraded renal electrolyte homeostasis and repressed immune-related pathways. In immune cells, miR-150-5p regulated NF-κB activation in T lymphocytes whereas miR-155-5p regulated mRNA splicing in antigen-presenting cells. Altogether, integrated omics enabled us to unravel new pathways involved in microvascular inflammation and suggests that metabolism modifications in tubular epithelial cells occur as a consequence of antibody-mediated rejection, beyond the nearby endothelial compartment.

Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection

“…Expression levels of significant enriched genes were calculated using AverageExpression function in Seurat according to each patient group. Validation scRNAseq dataset was compiled and analyzed as previously described 22, 23 .…”

Uncover diagnostic immunity/hypoxia/ferroptosis/epithelial mesenchymal transformation-related CCR5, CD86, CD8A, ITGAM, and PTPRC in kidney transplantation patients with allograft rejection

“…Activation of ATM is found in renal ischemia or reperfusion injury [ 80 ]. PEBP1, plays roles in anti-inflammatory effects under homeostatic/basal conditions, is associated with kidney allograft rejection [ 81 , 82 ]. This suggested the association of ferroptosis and allograft rejection after kidney transplantation.…”

Microvascular Inflammation of the Renal Allograft: A Reappraisal of the Underlying Mechanisms

“…The associated raw counts or matrices were downloaded from the Gene Expression Omnibus (GEO; GSE145927, ) and Kidney Precision Medicine Project ( ). The analysis was performed as previously published ( 67 , 68 ). (A) UMAP dimensionality reduction for the different cell type clusters identified by scRNA-seq analysis.…”