Limits...
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.

Show MeSH

Related in: MedlinePlus

miR-21 as a relevant miRNA involved in kidney fibrosis.(A) Heat map representing the statistically significant (Bonferroni adjusted p-value <0.01) differentially expressed microRNAs in kidneys with unilateral ureteral obstruction (UUO 28 Days) compared to control kidneys (sham). n = 4 mice in each group. (B) Differential expression of miR-29c, miR-30b, miR-200a, miR-192, miR-342-3p, miR-205 and miR-21 in UUO mouse model (array) and in human fibrotic kidneys (quantitative PCR, qPCR). Results are indicated as mean of log2 (injured kidneys versus control kidneys). Errors are presented as SEM. Significant differences in miRNA expression between injured and control kidneys, according to array or qPCR experiments were represented as follow: *p<0.05, **p<0.01. Mice: n = 4 in each group. Human: n = 10 in each group.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3585177&req=5

pone-0058014-g001: miR-21 as a relevant miRNA involved in kidney fibrosis.(A) Heat map representing the statistically significant (Bonferroni adjusted p-value <0.01) differentially expressed microRNAs in kidneys with unilateral ureteral obstruction (UUO 28 Days) compared to control kidneys (sham). n = 4 mice in each group. (B) Differential expression of miR-29c, miR-30b, miR-200a, miR-192, miR-342-3p, miR-205 and miR-21 in UUO mouse model (array) and in human fibrotic kidneys (quantitative PCR, qPCR). Results are indicated as mean of log2 (injured kidneys versus control kidneys). Errors are presented as SEM. Significant differences in miRNA expression between injured and control kidneys, according to array or qPCR experiments were represented as follow: *p<0.05, **p<0.01. Mice: n = 4 in each group. Human: n = 10 in each group.

Mentions: In a systematic approach to identify miRNAs involved in kidney fibrosis, we compared miRNA expression profile of fibrotic kidneys from mice 28 days after Unilateral Ureteral Obstruction (UUO) to that of control kidneys using microarray. MiRNAs were considered as statistically differentially expressed between injured and control kidneys at p-value below 0.01. We identified a panel of 50 miRNAs whose expression significantly differs between normal and fibrotic kidneys (Figure 1A and Table 1) of which 37 were down-regulated and 13 were up-regulated in mouse fibrotic kidneys. Most notable, among the up-regulated miRNAs were miR-205, miR-342 and miR-21, while miR-29c, miR-192, miR-30b and miR-200a were significantly down-regulated. To assess the clinical relevance of these findings, differential expression of these seven representative miRNAs in the mouse model was further evaluated by real-time PCR in human fibrotic kidneys (Figure 1B). In particular, our data showed a strong up-regulation of miR-21 in the injured kidney (fold change of 3 between injured and control kidneys), a miRNA known to exert major pathogenic effects in tissue fibrosis [14], [23]–[24]. Noteworthy, in fibrotic kidneys, miR-21 exhibited the highest expression level. Then, the following experiments focused on miR-21 implication in renal fibrosis.


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 as a relevant miRNA involved in kidney fibrosis.(A) Heat map representing the statistically significant (Bonferroni adjusted p-value <0.01) differentially expressed microRNAs in kidneys with unilateral ureteral obstruction (UUO 28 Days) compared to control kidneys (sham). n = 4 mice in each group. (B) Differential expression of miR-29c, miR-30b, miR-200a, miR-192, miR-342-3p, miR-205 and miR-21 in UUO mouse model (array) and in human fibrotic kidneys (quantitative PCR, qPCR). Results are indicated as mean of log2 (injured kidneys versus control kidneys). Errors are presented as SEM. Significant differences in miRNA expression between injured and control kidneys, according to array or qPCR experiments were represented as follow: *p<0.05, **p<0.01. Mice: n = 4 in each group. Human: n = 10 in each group.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0058014-g001: miR-21 as a relevant miRNA involved in kidney fibrosis.(A) Heat map representing the statistically significant (Bonferroni adjusted p-value <0.01) differentially expressed microRNAs in kidneys with unilateral ureteral obstruction (UUO 28 Days) compared to control kidneys (sham). n = 4 mice in each group. (B) Differential expression of miR-29c, miR-30b, miR-200a, miR-192, miR-342-3p, miR-205 and miR-21 in UUO mouse model (array) and in human fibrotic kidneys (quantitative PCR, qPCR). Results are indicated as mean of log2 (injured kidneys versus control kidneys). Errors are presented as SEM. Significant differences in miRNA expression between injured and control kidneys, according to array or qPCR experiments were represented as follow: *p<0.05, **p<0.01. Mice: n = 4 in each group. Human: n = 10 in each group.
Mentions: In a systematic approach to identify miRNAs involved in kidney fibrosis, we compared miRNA expression profile of fibrotic kidneys from mice 28 days after Unilateral Ureteral Obstruction (UUO) to that of control kidneys using microarray. MiRNAs were considered as statistically differentially expressed between injured and control kidneys at p-value below 0.01. We identified a panel of 50 miRNAs whose expression significantly differs between normal and fibrotic kidneys (Figure 1A and Table 1) of which 37 were down-regulated and 13 were up-regulated in mouse fibrotic kidneys. Most notable, among the up-regulated miRNAs were miR-205, miR-342 and miR-21, while miR-29c, miR-192, miR-30b and miR-200a were significantly down-regulated. To assess the clinical relevance of these findings, differential expression of these seven representative miRNAs in the mouse model was further evaluated by real-time PCR in human fibrotic kidneys (Figure 1B). In particular, our data showed a strong up-regulation of miR-21 in the injured kidney (fold change of 3 between injured and control kidneys), a miRNA known to exert major pathogenic effects in tissue fibrosis [14], [23]–[24]. Noteworthy, in fibrotic kidneys, miR-21 exhibited the highest expression level. Then, the following experiments focused on miR-21 implication in renal fibrosis.

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