title: Increased circulating miR-21 levels are associated with kidney fibrosis.
abstract: MicroRNAs (miRNAs) are a class of noncoding RNA acting at a post-transcriptional level to control the expression of large sets of target mRNAs. While there is evidence that miRNAs deregulation plays a causative role in various complex disorders, their role in fibrotic kidney diseases is largely unexplored. Here, we found a strong up-regulation of miR-21 in the kidneys of mice with unilateral ureteral obstruction and also in the kidneys of patients with severe kidney fibrosis. In addition, mouse primary fibroblasts derived from fibrotic kidneys exhibited higher miR-21 expression level compared to those derived from normal kidneys. Expression of miR-21 in normal primary kidney fibroblasts was induced upon TGFβ exposure, a key growth factor involved in fibrogenesis. Finally, ectopic expression of miR-21 in primary kidney fibroblasts was sufficient to promote myofibroblast differentiation. As circulating miRNAs have been suggested as promising non-invasive biomarkers, we further assess whether circulating miR-21 levels are associated with renal fibrosis using sera from 42 renal transplant recipients, categorized according to their renal fibrosis severity, evaluated on allograft biopsies (Interstitial Fibrosis/Tubular Atrophy (IF/TA). Circulating miR-21 levels are significantly increased in patients with severe IF/TA grade (IF/TA grade 3: 3.0±1.0 vs lower grade of fibrosis: 1.5±1.2; p = 0.001). By contrast, circulating miR-21 levels were not correlated with other renal histological lesions. In a multivariate linear regression model including IF/TA grade and estimated GFR, independent associations were found between circulating miR-21 levels and IF/TA score (ß = 0.307, p = 0.03), and between miR-21 levels and aMDRD (ß = -0.398, p = 0.006). Altogether, these data suggest miR-21 has a key pathogenic role in kidney fibrosis and may represent a novel, predictive and reliable blood marker of kidney fibrosis.
authors.affiliation: EA4483, Département de Biochimie et Biologie Moléculaire, Faculté de Médecine H Warembourg, Pôle Recherche, Lille, France. francois.glowacki@chru-lille.fr
authors.forename: François
authors.initials: F
authors.lastname: Glowacki
authors.forename: Grégoire
authors.initials: G
authors.lastname: Savary
authors.forename: Viviane
authors.initials: V
authors.lastname: Gnemmi
authors.forename: David
authors.initials: D
authors.lastname: Buob
authors.forename: Cynthia
authors.initials: C
authors.lastname: Van der Hauwaert
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lo-Guidice
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bouyé
authors.forename: Marc
authors.initials: M
authors.lastname: Hazzan
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pottier
authors.forename: Michaël
authors.initials: M
authors.lastname: Perrais
authors.forename: Sébastien
authors.initials: S
authors.lastname: Aubert
authors.forename: Christelle
authors.initials: C
authors.lastname: Cauffiez
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics; D008875:Middle Aged
chemical_list: D015415:Biomarkers; C524940:MIRN21 microRNA, human; D035683:MicroRNAs