title: Identification of urinary exosomal noncoding RNAs as novel biomarkers in chronic kidney disease.
abstract: In chronic kidney disease (CKD), the decline in the glomerular filtration rate is associated with increased morbidity and mortality and thus poses a major challenge for healthcare systems. While the contribution of tissue-derived miRNAs and mRNAs to CKD progression has been extensively studied, little is known about the role of urinary exosomes and their association with CKD. Exosomes are small, membrane-derived endocytic vesicles that contribute to cell-to-cell communication and are present in various body fluids, such as blood or urine. Next-generation sequencing approaches have revealed that exosomes are enriched in noncoding RNAs and thus exhibit great potential for sensitive nucleic acid biomarkers in various human diseases. Therefore, in this study we aimed to identify urinary exosomal ncRNAs as novel biomarkers for diagnosis of CKD. Since up to now most approaches have focused on the class of miRNAs, we extended our analysis to several other noncoding RNA classes, such as tRNAs, tRNA fragments (tRFs), mitochondrial tRNAs, or lincRNAs. For their computational identification from RNA-seq data, we developed a novel computational pipeline, designated as ncRNASeqScan. By these analyses, in CKD patients we identified 30 differentially expressed ncRNAs, derived from urinary exosomes, as suitable biomarkers for early diagnosis. Thereby, miRNA-181a appeared as the most robust and stable potential biomarker, being significantly decreased by about 200-fold in exosomes of CKD patients compared to healthy controls. Using a cell culture system for CKD indicated that urinary exosomes might indeed originate from renal proximal tubular epithelial cells.
authors.affiliation: Division of Genomics and RNomics, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Rimpi
authors.initials: R
authors.lastname: Khurana
authors.affiliation: Division of Genomics and RNomics, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Glory
authors.initials: G
authors.lastname: Ranches
authors.affiliation: Division of Genomics and RNomics, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Schafferer
authors.affiliation: Division of Genomics and RNomics, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Melanie
authors.initials: M
authors.lastname: Lukasser
authors.affiliation: Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Michael
authors.identifier: 0000-0002-7896-2600
authors.initials: M
authors.lastname: Rudnicki
authors.affiliation: Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Gert
authors.initials: G
authors.lastname: Mayer
authors.affiliation: Division of Genomics and RNomics, Biocenter, Medical University Innsbruck, 6020 Innsbruck, Austria.|i-med GenomeSeq Core, 6020 Innsbruck, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hüttenhofer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000652:urine; D016022:Case-Control Studies; D042241:Early Diagnosis; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D055354:Exosomes / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D005919:Glomerular Filtration Rate; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000652:urine*; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D012313:RNA / Q000652:urine; D062085:RNA, Long Noncoding / Q000652:urine; D000077278:RNA, Mitochondrial; D012343:RNA, Transfer / Q000652:urine; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis* / Q000473:pathology / Q000652:urine; D017423:Sequence Analysis, RNA; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D000077278:RNA, Mitochondrial; D012313:RNA; D012343:RNA, Transfer
keywords: chronic kidney disease; lincRNAs; miRNAs; ncRNAs; sequencing; tRFs; tRNAs; urinary exosomes