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Differential expression of urinary exosomal microRNAs in IgA nephropathy.

ABSTRACT: BACKGROUND:Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis in the world. Reliable biomarkers are required for the non-invasive diagnosis and monitoring of IgAN. This study aims to investigate the difference in urinary exosomal microRNA (miRNA) expression profiles between patients with IgA nephropathy (IgAN) and healthy controls, which may provide clues to identify novel potential non-invasive miRNA biomarkers for renal diseases. METHODS:Urine samples were collected from eighteen healthy controls and eighteen patients with IgAN. Differential centrifugation was performed to isolate exosomes from urine samples. High-throughput sequencing and real-time quantitative polymerase chain reaction (RT-qPCR) were sequentially used to screen and further validate miRNA expression profiles in urinary exosomes of patients with IgAN in two independent cohorts. RESULTS:Urinary exosomes were successfully isolated to obtain exosomal miRNAs. MiR-215-5p and miR-378i were significantly upregulated in urinary exosomes of patients with IgAN compared with healthy controls (P<.01), while miR-29c and miR-205-5p were significantly downregulated (P<.05). MiR-215-5p, miR-378i, miR-365b-3p and miR-135b-5p were found to have altered expression in patients with IgAN from validation cohorts, which was consistent with the high-throughput sequencing analysis. CONCLUSION:This study suggests that there is a significant difference in urinary exosomal miRNA profiles between patients with IgAN and healthy controls. These exosomal miRNAs, such as miR-29c, miR-146a and miR-205 may potentially serve as novel non-invasive biomarkers for IgAN.

SUBMITTER: Min QH

PROVIDER: S-EPMC6816951 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Differential expression of urinary exosomal microRNAs in IgA nephropathy.

Min Qing-Hua QH Chen Xi-Min XM Zou Ye-Qing YQ Zhang Jing J Li Jing J Wang Yan Y Li Shu-Qi SQ Gao Qiu-Fang QF Sun Fan F Liu Jing J Xu Yan-Mei YM Lin Jin J Huang Lin-Feng LF Huang Bo B Wang Xiao-Zhong XZ

Journal of clinical laboratory analysis 20170406 2

<h4>Background</h4>Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis in the world. Reliable biomarkers are required for the non-invasive diagnosis and monitoring of IgAN. This study aims to investigate the difference in urinary exosomal microRNA (miRNA) expression profiles between patients with IgA nephropathy (IgAN) and healthy controls, which may provide clues to identify novel potential non-invasive miRNA biomarkers for renal diseases.<h4>Methods</h4>Ur ...[more]

PMID: 28383146

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Project description:Background. MicroRNAs (miRNAs) have been found in virtually all body fluids and used successfully as biomarkers for various diseases. Evidence indicates that miRNAs have important roles in IgA nephropathy (IgAN), a major cause of renal failure. In this study, we looked for differentially expressed miRNAs in IgAN and further evaluated the correlations between candidate miRNAs and the severity of IgAN. Methods. Microarray and RT-qRCR (real-time quantitative polymerase chain reaction) were sequentially used to screen and further verify miRNA expression profiles in urinary sediments of IgAN patients in two independent cohorts. The screening cohort consisted of 32 urine samples from 18 patients with IgAN, 4 patients with MN (membranous nephropathy), 4 patients with MCD (minimal changes disease) and 6 healthy subjects; the validation cohort consisted of 102 IgAN patients, 41 MN patients, 27 MCD patients and 34 healthy subjects. The renal pathological lesions of patients with IgAN were evaluated according to Lee's grading system and Oxford classification. Results. At the screening phase, significance analysis of microarrays analysis showed that no miRNA was differentially expressed in the IgAN group compared to all control groups. But IgAN grade I-II and III subgroups (according to Lee's grading system) shared dysregulation of two miRNAs (miR-3613-3p and miR-4668-5p). At the validation phase, RT-qPCR results showed that urinary level of miR-3613-3p was significantly lower in IgAN than that in MN, MCD and healthy controls (0.47, 0.44 and 0.24 folds, respectively, all P < 0.01 by Mann-Whitney U test); urinary level of miR-4668-5p was also significantly lower in IgAN than that in healthy controls (0.49 fold, P < 0.01). Significant correlations were found between urinary levels of miR-3613-3p with 24-hour urinary protein excretion (Spearman r = 0.50, P = 0.034), eGFR (estimated glomerular filtration rate) (r = - 0.48, P = 0.043) and Lee's grades (r = 0.57, P = 0.014). Similarly, miR-4668-5p was significantly correlated with eGFR (r = - 0.50, P = 0.034) and Lee's grades (r = 0.57, P = 0.013). For segmental glomerulosclerosis according to Oxford classification, patients scored as S0 had significantly lower levels of urinary miR-3613-3p and miR-4668-5p than those scored as S1 (0.41 and 0.43 folds, respectively, all P < 0.05). Conclusions. The expression profile of miRNAs was significantly altered in urinary sediments from patients with IgAN. Urinary expression of miR-3613-3p was down-regulated in patients with IgAN. Moreover, urinary levels of both miR-3613-3p and miR-4668-5p were correlated with disease severity. Further studies are needed to explore the roles of miR-3613-3p and miR-4668-5p in the pathogenesis and progression of IgA nephropathy.

Project description:BackgroundIgA nephropathy (IgAN) is one of the most common forms of idiopathic glomerular diseases and might lead to end-stage kidney disease. Accurate and non-invasive biomarkers for early diagnosis are required for early intervention and consequent therapy for IgAN patients. Because variance in the disease incidence and predisposing genes of IgAN has been detected among different ethnicities, the ethnicity factor should be considered in IgAN biomarker discovery. The differences in the protein profiles and pathological mechanisms of IgAN in patients of Uygur ethnicity need to be clearly illustrated.MethodsIn this study, we used urinary proteomics to discover candidate biomarkers of IgAN in patients of Uygur ethnicity. The urinary proteins from Uygur normal control and Uygur IgAN patients were extracted and analyzed using 2D-LC-MS/MS and isobaric tags for relative and absolute quantitation (iTRAQ) analysis.ResultsA total of 277 proteins were found to be differentially represented in Uygur IgAN compared with the respective normal controls. The bioinformatics analysis revealed that the immune response, cell survival, and complement system were activated in Uygur IgAN. Many differentially expressed proteins were found to be related to nephropathy and kidney injuries. Four candidate biomarkers were validated by Western blot, and these results were consistent with the iTRAQ results. ICAM1, TIMP1, SERPINC1 and ADIPOQ were upregulated in Uygur IgAN. Bioinformatic analysis revealed that the increase of ICAM1 and TIMP1 might be caused by IgAN, but the increase of SERPINC1 and ADIPOQ might be caused by proteinuria. SERPINC1 and ICAM1 were identified as the candidate biomarkers with excellent area-under-the-curve (AUC) values (0.84) for distinguishing Uygur IgAN from normal controls.ConclusionsUsing urinary proteomic analysis, we identified several candidate biomarkers for IgAN in patients of Uygur ethnicity. These results will prove helpful for exploring the pathological mechanism of IgAN in patients of Uygur ethnicity and for developing better treatments for these patients.

Project description:Background: IgA nephropathy (IgAN) is one of the most common forms of primary glomerulonephritis. Recent studies have indicated that small noncoding RNAs, such as tRNA-derived small RNAs (tsRNAs), might be novel biomarkers for glomerulonephritis. We therefore investigated the potential roles and possible functions of the tsRNAs in IgAN.Method: Peripheral blood mononuclear cells (PBMCs) were extracted from blood samples of the patients with IgAN and healthy control groups. The expression profiles of tsRNAs were assessed by small RNA sequencing (RNA-Seq) in PBMCs of the IgAN and control groups. Dysregulated tsRNAs were selected for validation by quantitative real-time polymerase chain reaction (qRT-PCR). Target gene prediction and enrichment were performed by bioinformatics analysis.Results: The results revealed that 143 significantly upregulated and 202 significantly downregulated tsRNAs were differentially altered in the IgAN group compared with the control group. Five upregulated tsRNAs (tRF-Val-AAC-007, tRF-Ala-AGC-063, tRF-Gln-CTG-010, tRF-Tyr-GTA-011 and tRF-Thr-AGT-007) and 3 downregulated tsRNAs (tiRNA-Val-TAC-004, tRF-Gly-CCC-005 and tRF-His-GTG-006) were selected for validation by qRT-PCR; the results were consistent with the sequencing data. Gene Ontology (GO) analysis revealed that the target genes predicted by upregulated tsRNAs were mostly enriched in "nucleic acid metabolic process,' "intracellular part,' and "ion binding,' whereas the target genes predicted by downregulated tsRNAs were mostly enriched in "regulation of cellular component organization,' "membrane-bound organelle,' and "ion binding.' Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the target genes predicted by upregulated tsRNAs were mostly enriched in "herpes simplex virus 1 infection,' whereas the target genes predicted by downregulated tsRNAs were mostly enriched in "circadian rhythm CONCLUSIONS:: The present study confirmed the differential expression of tsRNAs in patients with IgAN, and these dysregulated tsRNAs might be novel potential targets for the diagnosis and treatment of IgAN.

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Differential expression of urinary exosomal microRNAs in IgA nephropathy.

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Differential expression of urinary exosomal microRNAs in IgA nephropathy.

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