title: Extracellular microRNA signature in chronic kidney disease.
abstract: MicroRNAs (miRNAs) are noncoding RNAs that regulate posttranscriptional gene expression. In this study we characterized the circulating and urinary miRNA pattern associated with reduced glomerular filtration rate, using Affymetrix GeneChip miR 4.0 in 28 patients with chronic kidney disease (CKD). Top miRNA discoveries from the human studies were validated in an Alb/TGFβ mouse model of CKD, and in rat renal proximal tubular cells (NRK52E) exposed to TGFβ1. Plasma and urinary levels of procollagen III N-terminal propeptide and collagen IV were elevated in patients with decreased estimated glomerular filtration rate (eGFR). Expression of 384 urinary and 266 circulatory miRNAs were significantly different between CKD patients with eGFR ≥30 vs. <30 ml·min-1·1.73 m-2Pathway analysis mapped multiple miRNAs to TGFβ signaling-related mRNA targets. Specifically, Let-7a was significantly downregulated, and miR-130a was significantly upregulated, in urine of patients with eGFR <30; miR-1825 and miR-1281 were upregulated in both urine and plasma of patients with decreased eGFR; and miR-423 was significantly downregulated in plasma of patients with decreased eGFR. miRNA expression in urine and plasma of Alb/TGFβ mice generally resembled and confirmed most, although not all, of the observations from the human studies. In response to TGFβ1 exposure, rat renal proximal tubular cells overexpressed miR-1825 and downregulated miR-423. Thus, miRNA are associated with kidney fibrosis, and specific urinary and plasma miRNA profile may have diagnostic and prognostic utility in CKD.
authors.affiliation: Division of Renal Diseases and Hypertension, The George Washington University School of Medicine, Washington, District of Columbia.
authors.forename: Jagdeesan
authors.initials: J
authors.lastname: Muralidharan
authors.affiliation: Division of Renal Diseases and Hypertension, The George Washington University School of Medicine, Washington, District of Columbia.
authors.forename: Ali
authors.initials: A
authors.lastname: Ramezani
authors.affiliation: Department of Exercise and Nutrition Sciences, George Washington University, Washington, District of Columbia.
authors.forename: Monica
authors.initials: M
authors.lastname: Hubal
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Washington, District of Columbia.
authors.forename: Susan
authors.initials: S
authors.lastname: Knoblach
authors.affiliation: Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Shashi
authors.initials: S
authors.lastname: Shrivastav
authors.affiliation: College of Veterinary Medicine, Western University of Health Sciences, Pomona, California.
authors.forename: Sara
authors.initials: S
authors.lastname: Karandish
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Washington, District of Columbia.
authors.forename: Richard
authors.initials: R
authors.lastname: Scott
authors.affiliation: University of Florida, School of Medicine, Miami, Florida.
authors.forename: Nirmal
authors.initials: N
authors.lastname: Maxwell
authors.affiliation: Department of Nephrology, Haseki Training and Research Hospital, Istanbul, Turkey; and.
authors.forename: Savas
authors.initials: S
authors.lastname: Ozturk
authors.affiliation: Division of Nephrology, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Beddhu
authors.affiliation: Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.affiliation: Division of Renal Diseases and Hypertension, The George Washington University School of Medicine, Washington, District of Columbia; draj@mfa.gwu.edu.
authors.forename: Dominic S
authors.initials: DS
authors.lastname: Raj
mesh_terms: D000328:Adult; D000368:Aged; D000418:Albumins / Q000235:genetics; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000097:blood / Q000235:genetics* / Q000652:urine; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000235:genetics* / Q000503:physiopathology / Q000652:urine; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D000418:Albumins; D005819:Genetic Markers; D035683:MicroRNAs; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1
keywords: TGFβ; chronic kidney disease; fibrosis