title: Urinary Xist is a potential biomarker for membranous nephropathy.
abstract: Membranous nephropathy (MN), a type of glomerular nephritis, is the most common cause of nephrotic syndrome in human adults. Changes in gene expression as a result of epigenetic dysregulation through long noncoding RNAs (lncRNAs) are increasingly being recognized as important factors in disease. Using an experimental MN mouse model, we identify the first dysregulated lncRNAs, Xist and NEAT1, whose levels are significantly upregulated in both tubular epithelial and glomerular cells. MN is also often characterized by glomerular podocyte injury. Treatment of a mouse podocyte cell line with lipopolysaccharides to induce injury resulted in the stable elevation of Xist, but not NEAT1 levels. In mice, the observed changes in Xist levels are specific: Xist can be effectively detected in urine, with a strong correlation to disease severity, but not serum in MN samples. We find that regulation of Xist may be controlled by post-translational modifications. H3K27me3 levels are significantly downregulated in mouse MN kidney, where chromatin immunoprecipitation experiments also showed decreased H3K27me3 at Xist promoter regions. Finally, we show that our findings in mice can be extended to human clinical samples. Urinary Xist is significantly elevated in urine samples from patients with different types of glomerular nephritis, including MN, compared to normal counterparts. Together, our results suggest that a reduction of H3K27me3 at Xist promoter regions leads to elevated levels of urinary Xist, which may be used as a biomarker to detect MN.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taiwan.
authors.forename: Yen-Sung
authors.initials: YS
authors.lastname: Huang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Hsieh
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taiwan.
authors.forename: Hsiu-Ming
authors.initials: HM
authors.lastname: Shih
authors.affiliation: Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taiwan.
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taiwan; Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taiwan. Electronic address: wucc@mail.ndmctsgh.edu.tw.
authors.forename: Chia-Chao
authors.initials: CC
authors.lastname: Wu
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000652:urine; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D015433:Glomerulonephritis, Membranous / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000652:urine; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000819:agonists / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D006657:Histones; D008070:Lipopolysaccharides; C577275:NEAT1 long non-coding RNA, mouse; D062085:RNA, Long Noncoding; C077885:XIST non-coding RNA
keywords: H3K27me3; LncRNA; Membranous nephropathy; Xist