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Increased circulating miR-21 levels are associated with kidney fibrosis.

Glowacki F, Savary G, Gnemmi V, Buob D, Van der Hauwaert C, Lo-Guidice JM, Bouyé S, Hazzan M, Pottier N, Perrais M, Aubert S, Cauffiez C - PLoS ONE (2013)

Bottom Line: While there is evidence that miRNAs deregulation plays a causative role in various complex disorders, their role in fibrotic kidney diseases is largely unexplored.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).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).

View Article: PubMed Central - PubMed

Affiliation: EA4483, Département de Biochimie et Biologie Moléculaire, Faculté de Médecine H Warembourg, Pôle Recherche, Lille, France. francois.glowacki@chru-lille.fr

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.

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miR-21 is up-regulated in kidneys from patients with severe kidney fibrosis.(A) miR-21 expression obtained by real time PCR in kidneys from patients with severe kidney fibrosis (cases n = 11) versus normal human kidneys (controls n = 12). RNU6B was used as normalizer. Data are expressed as mean ± SEM. * p<0.05. (B) In situ hybridization assay was performed to determine to determine the stromal localization of miR-21 and its colocalization with α-SMA in the kidney from detransplanted patients. Results represent one out of three independent experiments.
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pone-0058014-g004: miR-21 is up-regulated in kidneys from patients with severe kidney fibrosis.(A) miR-21 expression obtained by real time PCR in kidneys from patients with severe kidney fibrosis (cases n = 11) versus normal human kidneys (controls n = 12). RNU6B was used as normalizer. Data are expressed as mean ± SEM. * p<0.05. (B) In situ hybridization assay was performed to determine to determine the stromal localization of miR-21 and its colocalization with α-SMA in the kidney from detransplanted patients. Results represent one out of three independent experiments.

Mentions: Interestingly, miR-21 expression was strongly up-regulated in kidneys explanted from renal transplanted patients and exhibiting severe fibrosis on graft biopsies (Figure 4A). This tissue expression was specifically localized in myofibroblasts-rich areas, as determined by α-smooth muscle actin immunostaining (Figure 4B).


Increased circulating miR-21 levels are associated with kidney fibrosis.

Glowacki F, Savary G, Gnemmi V, Buob D, Van der Hauwaert C, Lo-Guidice JM, Bouyé S, Hazzan M, Pottier N, Perrais M, Aubert S, Cauffiez C - PLoS ONE (2013)

miR-21 is up-regulated in kidneys from patients with severe kidney fibrosis.(A) miR-21 expression obtained by real time PCR in kidneys from patients with severe kidney fibrosis (cases n = 11) versus normal human kidneys (controls n = 12). RNU6B was used as normalizer. Data are expressed as mean ± SEM. * p<0.05. (B) In situ hybridization assay was performed to determine to determine the stromal localization of miR-21 and its colocalization with α-SMA in the kidney from detransplanted patients. Results represent one out of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585177&req=5

pone-0058014-g004: miR-21 is up-regulated in kidneys from patients with severe kidney fibrosis.(A) miR-21 expression obtained by real time PCR in kidneys from patients with severe kidney fibrosis (cases n = 11) versus normal human kidneys (controls n = 12). RNU6B was used as normalizer. Data are expressed as mean ± SEM. * p<0.05. (B) In situ hybridization assay was performed to determine to determine the stromal localization of miR-21 and its colocalization with α-SMA in the kidney from detransplanted patients. Results represent one out of three independent experiments.
Mentions: Interestingly, miR-21 expression was strongly up-regulated in kidneys explanted from renal transplanted patients and exhibiting severe fibrosis on graft biopsies (Figure 4A). This tissue expression was specifically localized in myofibroblasts-rich areas, as determined by α-smooth muscle actin immunostaining (Figure 4B).

Bottom Line: While there is evidence that miRNAs deregulation plays a causative role in various complex disorders, their role in fibrotic kidney diseases is largely unexplored.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).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).

View Article: PubMed Central - PubMed

Affiliation: EA4483, Département de Biochimie et Biologie Moléculaire, Faculté de Médecine H Warembourg, Pôle Recherche, Lille, France. francois.glowacki@chru-lille.fr

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.

Show MeSH
Related in: MedlinePlus