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      Urinary sediment miRNAs reflect tubulointerstitial damage and therapeutic response in IgA nephropathy

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          Abstract

          Background

          Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide. The clinical spectrum of IgAN varies from minor urinary abnormalities to rapidly progressive renal failure. Evaluation of the disease by repeated renal biopsy is not practical due to its invasive procedure. Urinary sediment miRNAs promise to serve as non-invasive biomarkers to assess kidney injury of IgAN.

          Methods

          Fifty two biopsy-proven IgAN patients and twenty five healthy controls were enrolled in the study. Urinary sediment miRNAs were extracted. Expressions of miR-34a, miR-205, miR-21, miR-146a and miR-155 were quantified by real-time quantitative polymerase chain reaction (RT-QPCR). The receiver operating characteristic (ROC) curve was used to investigate the value of the miRNAs for predicting diagnosis of IgAN and evaluating histopathological injury. The patients were treated according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and followed up. The roles of miRNAs in reflecting therapeutic efficacy and disease progression were analyzed.

          Results

          1. The IgAN group had significantly lower urinary miR-34a, miR-205, and miR-155, but higher miR-21 levels than controls. The ROC revealed that urinary miR-34a ≤ 0.047, miR-205 ≤ 0.209, miR-21 ≥ 0.461 and miR-155 ≤ 0.002 could distinguish patients with IgAN from healthy ones. In addition, miR-205 ≤ 0.125 and miR-21 ≥ 0.891 can distinguish IgAN patients with severe tubular atrophy/interstitial fibrosis from those with mild tubular atrophy/interstitial fibrosis. 2. After a mean 15.19 months follow-up, the reduction of proteinuria (g/24 h/year) was positively correlated with baseline urinary miR-21 and inversely correlated with miR-205. The levels of baseline eGFR and miR-205 in the complete remission group were significantly higher than non-complete remission group ( p < 0.001; p = 0.018), while proteinuria, miR-21 and miR-146a were lower than non-complete remission group ( p = 0.002; p = 0.021; p = 0.009). But multivariate analysis revealed that only baseline eGFR correlated with the remission of IgAN ( p = 0.001, OR = 1.042).

          Conclusions

          The levels of some urinary sediment miRNAs, especially baseline miR-21 and miR-205, may be used as potential prognostic markers for evaluating the tubulointerstitial damage of IgAN. Furthermore, baseline levels of urinary miRNAs may be predictors of therapeutic efficacy and disease progression.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12882-017-0482-0) contains supplementary material, which is available to authorized users.

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          Most cited references26

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          Mechanisms of tubulointerstitial fibrosis.

          The pathologic paradigm for renal progression is advancing tubulointerstitial fibrosis. Whereas mechanisms underlying fibrogenesis have grown in scope and understanding in recent decades, effective human treatment to directly halt or even reverse fibrosis remains elusive. Here, we examine key features mediating the molecular and cellular basis of tubulointerstitial fibrosis and highlight new insights that may lead to novel therapies. How to prevent chronic kidney disease from progressing to renal failure awaits even deeper biochemical understanding.
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            Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis.

            MicroRNAs (miRNA) have recently emerged as a new class of modulators of gene expression. In this study we investigated the expression, regulation, and function of miR-155 and miR-146a in rheumatoid arthritis (RA) synovial fibroblasts (RASFs) and RA synovial tissue. Locked nucleic acid microarray was used to screen for differentially expressed miRNA in RASFs treated with tumor necrosis factor alpha (TNFalpha). TaqMan-based real-time polymerase chain reaction was applied to measure the levels of miR-155 and miR-146a. Enforced overexpression of miR-155 was used to investigate the function of miR-155 in RASFs. Microarray analysis of miRNA expressed in RASFs treated with TNFalpha revealed a prominent up-regulation of miR-155. Constitutive expression of both miR-155 and miR-146a was higher in RASFs than in those from patients with osteoarthritis (OA), and expression of miR-155 could be further induced by TNFalpha, interleukin-1beta, lipopolysaccharide, poly(I-C), and bacterial lipoprotein. The expression of miR-155 in RA synovial tissue was higher than in OA synovial tissue. Enforced expression of miR-155 in RASFs was found to repress the levels of matrix metalloproteinase 3 (MMP-3) and reduce the induction of MMPs 3 and 1 by Toll-like receptor ligands and cytokines. Moreover, compared with monocytes from RA peripheral blood, RA synovial fluid monocytes displayed higher levels of miR-155. This study provides the first description of increased expression of miRNA miR-155 and miR-146a in RA. Based on these findings, we postulate that the inflammatory milieu may alter miRNA expression profiles in resident cells of the rheumatoid joints. Considering the repressive effect of miR-155 on the expression of MMPs 3 and 1 in RASFs, we hypothesize that miR-155 may be involved in modulation of the destructive properties of RASFs.
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              miR-155 gene: a typical multifunctional microRNA.

              In the last years small RNA molecules, i.e. microRNA (miRNA) encoded by miR genes, have been found to play a crucial role in regulating gene expression of a considerable part of plant's and animal's genome. Here, we report the essential information on biogenesis of miRNAs and recent evidence on their important role in human diseases. Emphasis has been given to miR-155, since this molecule represents a typical multifunctional miRNA. Recent data indicate that miR-155 has distinct expression profiles and plays a crucial role in various physiological and pathological processes such as haematopoietic lineage differentiation, immunity, inflammation, cancer, and cardiovascular diseases. Moreover, miR-155 has been found to be implicated in viral infections, particularly in those caused by DNA viruses. The available experimental evidence indicating that miR-155 is over expressed in a variety of malignant tumors allows us to include this miRNA in the list of genes of paramount importance in cancer diagnosis and prognosis. Exogenous molecular control in vivo of miR-155 expression could open up new ways to restrain malignant growth and viral infections, or to attenuate the progression of cardiovascular diseases.
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                Author and article information

                Contributors
                liangshuang301@outlook.com
                +86-10-66935462 , caiguangyan@sina.com
                loveduanzhiyu@163.com
                liushuwen@me-email.com
                wujie301@126.com
                lvyang1978@hotmail.com
                hou301@126.com
                sdwslf@163.com
                xg301301@163.com
                xmchen301@126.com
                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central (London )
                1471-2369
                15 February 2017
                15 February 2017
                2017
                : 18
                : 63
                Affiliations
                ISNI 0000 0004 1761 8894, GRID grid.414252.4, Department of Nephrology, , Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, ; 28 Fuxing Road, Beijing, 100853 China
                Article
                482
                10.1186/s12882-017-0482-0
                5312444
                28201996
                23bfc947-5a0c-4e70-8583-ec9abb607425
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 28 August 2016
                : 9 February 2017
                Funding
                Funded by: 973 program
                Award ID: 2013CB530800
                Funded by: 863 program
                Award ID: 2012AA02A512
                Funded by: the Science and Technology Project of Beijing
                Award ID: D131100004713003
                Funded by: NSFC
                Award ID: 81171645
                Funded by: National Key Technology RD Program
                Award ID: 2013BAI09B05
                Award ID: 2011BAI10B00
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2017

                Nephrology
                iga nephropathy,urinary sediment,mirnas,tubulointerstitial damage,therapeutic response
                Nephrology
                iga nephropathy, urinary sediment, mirnas, tubulointerstitial damage, therapeutic response

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