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

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.

Abstract licence: CC BY

1. 16.

   Gateways to the FANTOM5 promoter level mammalian expression atlas · 2015

2. 20.

   Sparse Partial Least Squares Regression for Simultaneous Dimension Reduction and Variable Selection · 2010

3. 25.

   Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages · 2016

4. 38.

   A single-nucleus RNA-sequencing pipeline to decipher the molecular anatomy and pathophysiology of human kidneys · 2019

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