Dataset Information

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.

SUBMITTER: Tinel C

PROVIDER: S-EPMC8593247 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Tinel Claire C Lamarthée Baptiste B Callemeyn Jasper J Van Loon Elisabet E Sauvaget Virginia V Morin Lise L Aouni Laïla L Rabant Marion M Gwinner Wilfried W Marquet Pierre P Naesens Maarten M Anglicheau Dany D

Frontiers in immunology 20211102

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 coh ...[more]

PMID: 34795664

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Project description:Lonicera japonica Thunb. is an important medicinal plant. The secondary metabolites in L. japonica are diverse and vary in levels during development, leading to the ambiguous evaluation for its medical value. In order to reveal the regulatory mechanism of secondary metabolites during the flowering stages, transcriptomic, proteomic, and metabolomic analyses were performed. The integration analysis of omic-data illustrated that the metabolic changes over the flower developmental stages were mainly involved in sugar metabolism, lipopolysaccharide biosynthesis, carbon conversion, and secondary metabolism. Further proteomic analysis revealed that uniquely identified proteins were mainly involved in glycolysis/phenylpropanoids and tricarboxylic acid cycle/terpenoid backbone pathways in early and late stages, respectively. Transketolase was commonly identified in the 5 developmental stages and 2-fold increase in gold flowering stage compared with juvenile bud stage. Simple phenylpropanoids/flavonoids and 1-deoxy-D-xylulose-5-phosphate were accumulated in early stages and upregulated in late stages, respectively. These results indicate that phenylpropanoids were accumulated attributing to the activated glycolysis process in the early stages, while the terpenoids biosynthetic pathways might be promoted by the transketolase-contained regulatory circuit in the late stages of L. japonica flower development. BIOLOGICAL SIGNIFICANCE: Lonicera japonica Thunb. is a native species in the East Asian and used in traditional Chinese medicine. In order to reveal the regulatory mechanism of secondary metabolites during the flowering stages, transcriptomic, proteomic, and metabolomic analyses were performed. The integration analysis of omic-data illustrated that the metabolic changes over the flower developmental stages were mainly involved in sugar metabolism, lipopolysaccharide biosynthesis, carbon conversion, and secondary metabolism. Our results indicate that phenylpropanoids were accumulated attributing to the activated glycolysis process in the early stages, while the terpenoids biosynthetic pathways might be promoted by the transketolase-contained regulatory circuit in the late stages of L. japonica flower development.

Project description:BackgroundEndothelial dysfunction is an early manifestation of cardiovascular disease (CVD) and consistently observed in patients with chronic kidney disease (CKD). We hypothesized that CKD is associated with systemic damage to the microcirculation, preceding macrovascular pathology. To assess the degree of "uremic microangiopathy", we have measured microvascular density in biopsies of the omentum of children with CKD.Patients and methodsOmental tissue was collected from 32 healthy children (0-18 years) undergoing elective abdominal surgery and from 23 age-matched cases with stage 5 CKD at the time of catheter insertion for initiation of peritoneal dialysis. Biopsies were analyzed by independent observers using either a manual or an automated imaging system for the assessment of microvascular density. Quantitative immunohistochemistry was performed for markers of autophagy and apoptosis, and for the abundance of the angiogenesis-regulating proteins VEGF-A, VEGF-R2, Angpt1 and Angpt2.ResultsMicrovascular density was significantly reduced in uremic children compared to healthy controls, both by manual imaging with a digital microscope (median surface area 0.61% vs. 0.95%, p<0.0021 and by automated quantification (total microvascular surface area 0.89% vs. 1.17% p = 0.01). Density measured by manual imaging was significantly associated with age, height, weight and body surface area in CKD patients and healthy controls. In multivariate analysis, age and serum creatinine level were the only independent, significant predictors of microvascular density (r2 = 0.73). There was no immunohistochemical evidence for apoptosis or autophagy. Quantitative staining showed similar expression levels of the angiogenesis regulators VEGF-A, VEGF-receptor 2 and Angpt1 (p = 0.11), but Angpt2 was significantly lower in CKD children (p = 0.01).ConclusionsMicrovascular density is profoundly reduced in omental biopsies of children with stage 5 CKD and associated with diminished Angpt2 signaling. Microvascular rarefaction could be an early systemic manifestation of CKD-induced cardiovascular disease.

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Dataset Information

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

Publications

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

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