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Specific normalization of urinary mRNAs reveals genome-wide patterns associated with renal allograft subclinical injury

ABSTRACT: urinary mRNA quantification using an Agilent 60k microarray in 26 stable kidney transplant patients with or without renal partial Epithelial to Mesenchymal Transition Subclinical pathological features on the 3-month biopsy of renal allografts predict a poor prognosis, but it is unclear whether surveillance biopsies are beneficial. Non-invasive biomarkers are wanted, and urinary pellet RNA quantification of selected candidate genes has been used with some success do detect overt rejection. We performed a mRNA microarray study using different normalization methods on the urinary cell pellet to evaluate the feasibility of using urine to detect renal partial epithelial mesenchymal transition of the renal allograft (renal pEMT) non-invasively in a group of 26 stable transplanted patients. We found that, when using a novel method of normalization by Upk1a mRNA, renal pEMT of the renal allograft was associated in urine with differential expression of genes belonging to predefined gene sets of kidney-expressed genes and epithelial mesenchymal transition genes. An unbiased pathway analysis revealed that the immune response was the main urinary biological process associated with pEMT in the kidney. In urine from patients with pristine biopsies, pEMT was not associated with inflammation, but with reduced metabolic functions. Thus, we show that pEMT translates into specific UPK1a-normalized mRNA patterns in urine and use genome-wide analyses to characterize underlying molecular patterns, i.e. increased inflammation and decreased metabolic functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE89652 | GEO | 2017/09/01

SECONDARY ACCESSION(S): PRJNA352832

REPOSITORIES: GEO

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Project description:Background: Although the clinical fingerprints of the BK virus (BKV) infection in kidney transplant recipients (KTRs) has been well documented, the systemic biological machinery involved in this complication is still poorly recognized. Proteomics analysis of urinary extracellular vesicles (EVs) can allow us to better address this knowledge gap. Methods: Twenty-nine adult KTRs with normal allograft function affected by BKV infection (15 with only viremia, 14 with viruria and viremia) and 15 controls (CTR) were enrolled and randomly divided in a training cohort (12 BKV and 6 CTR) used for the mass spectrometry analysis of the EVs protein content and a testing cohort(17 BKV and 9 CTR) used for the biological validation of the proteomic results by ELISA. Results: Mass spectrometry analysis revealed a large protein enrichment (more than 1500) in urinary EVs of BKV patients and controls. Pathway analysis by GSEA revealed that several biological gene ontologies (including immunity, complement activation, renal fibrosis, tubular diseases, epithelial to mesenchymal transition) were able to discriminate BKV versus CTR. Kinase was the only gene ontology annotation term negatively enriched in BKV (with SLK being the most down-regulated protein in BKV). Statistical analysis, then, identified a core panel of 70 proteins (including DNASE2, F12, AGT, CTSH, C4A, C7, FABP4 and BPNT1) able to discriminate the two study groups. Instead, although a set of proteins were able to differentiate patients with BKV viruria from those with both viremia-viruria, the urinary proteomic profile of these patients resulted quite similar between the two sub-groups. ELISA for SLK and ELISA for BPNT1 and DNASE2 validated proteomics results. Conclusions: Our study demonstrated that BK virus infection is able to significantly modify the urinary EVs proteomic profile of KTRs also in a very early stage of the disease (when patients still have normal allograft function and only BK viruria) suggesting, whether possible, to start an early preventive therapeutic approach to minimize the risk of the disease progression. Moreover, some 3 of our identified proteins could be employed in future as early urinary biomarkers and/or new therapeutic targets.

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Specific normalization of urinary mRNAs reveals genome-wide patterns associated with renal allograft subclinical injury

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