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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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Circulating miR-21 is a potential biomarker of kidney fibrosis.(A, B) Circulating miR-21 levels are not affected by patient gender or age. (C, D) miR-21 circulating levels are increased in patients with high grade of Interstitial Fibrosis/Tubular Atrophy grade 3 (IF/TA grade 3). MiR-16 was used as normalizer. (E) Receiver operating characteristic curve analysis displaying the diagnostic power in predicting severe kidney fibrosis (IF/TA grade 3) of circulating miR-21 levels (area under the curve (AUC): 0.891). (F) Significant correlation (p<0.003, R = −0.451) between circulating miR-21 and glomerular filtration rate (based on MDRD formula) in patients with various grade of kidney fibrosis is shown. Data are expressed as mean ± SEM. ** p<0.01.
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pone-0058014-g005: Circulating miR-21 is a potential biomarker of kidney fibrosis.(A, B) Circulating miR-21 levels are not affected by patient gender or age. (C, D) miR-21 circulating levels are increased in patients with high grade of Interstitial Fibrosis/Tubular Atrophy grade 3 (IF/TA grade 3). MiR-16 was used as normalizer. (E) Receiver operating characteristic curve analysis displaying the diagnostic power in predicting severe kidney fibrosis (IF/TA grade 3) of circulating miR-21 levels (area under the curve (AUC): 0.891). (F) Significant correlation (p<0.003, R = −0.451) between circulating miR-21 and glomerular filtration rate (based on MDRD formula) in patients with various grade of kidney fibrosis is shown. Data are expressed as mean ± SEM. ** p<0.01.

Mentions: Patients were categorized in different groups according to renal allograft fibrosis score based on Banff classification as detailed in Table 2. To exclude potential biases, we determined to what extent serum miRNA levels were confounded with the baseline patient characteristics. Serum miR-21 levels were not different according to patient gender or age (Figure 5A–B). Serum levels of miR-21 in patients with severe fibrosis (IF/TA grade 3) were significantly elevated when compared to other patients (IF/TA grades 0, 1 and 2) (3.0±1.0 vs 1.5±1.2; p<0.001) (Figure 5C). As shown in Figure 5D, circulating miR-21 levels gradually increased with IF/TA fibrosis grade (R = 0.376, p = 0.01). The predictive power of circulating miR-21 levels for the presence of severe kidney fibrosis (IF/TA grade 3) was evaluated by ROC-analysis (Figure 5E). This revealed an area under the curve of 0.891 (95% confidence interval, 0.792–0.989). By contrast, circulating miR-21 levels were not correlated with other Banff criteria related to acute inflammation, chronic vascular or glomerular changes (Figure 6). Subsequently, we assessed the correlation between serum levels of miR-21 with patient renal function. MiR-21 correlated significantly to both estimated glomerular filtration rate (GFR) evaluated by aMDRD formula (regression coefficient R = −0.451, p = 0.003, Figure 5F) and plasmatic creatinine (R = 0.490, p<0.0001, not shown). In a model including IF/TA grade and estimated GFR, multivariate linear regression described independent associations between circulating miR-21 levels and IF/TA score (ß = 0.307, p = 0.03), as well as miR-21 levels and aMDRD (ß = −0.398, p = 0.006). By contrast, no correlation was observed between miR-21 levels and cellular lysis markers (as lactate dehydrogenase, alanine amino transferase and aspartate amino transferase) or C Reactive Protein.


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)

Circulating miR-21 is a potential biomarker of kidney fibrosis.(A, B) Circulating miR-21 levels are not affected by patient gender or age. (C, D) miR-21 circulating levels are increased in patients with high grade of Interstitial Fibrosis/Tubular Atrophy grade 3 (IF/TA grade 3). MiR-16 was used as normalizer. (E) Receiver operating characteristic curve analysis displaying the diagnostic power in predicting severe kidney fibrosis (IF/TA grade 3) of circulating miR-21 levels (area under the curve (AUC): 0.891). (F) Significant correlation (p<0.003, R = −0.451) between circulating miR-21 and glomerular filtration rate (based on MDRD formula) in patients with various grade of kidney fibrosis is shown. Data are expressed as mean ± SEM. ** p<0.01.
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pone-0058014-g005: Circulating miR-21 is a potential biomarker of kidney fibrosis.(A, B) Circulating miR-21 levels are not affected by patient gender or age. (C, D) miR-21 circulating levels are increased in patients with high grade of Interstitial Fibrosis/Tubular Atrophy grade 3 (IF/TA grade 3). MiR-16 was used as normalizer. (E) Receiver operating characteristic curve analysis displaying the diagnostic power in predicting severe kidney fibrosis (IF/TA grade 3) of circulating miR-21 levels (area under the curve (AUC): 0.891). (F) Significant correlation (p<0.003, R = −0.451) between circulating miR-21 and glomerular filtration rate (based on MDRD formula) in patients with various grade of kidney fibrosis is shown. Data are expressed as mean ± SEM. ** p<0.01.
Mentions: Patients were categorized in different groups according to renal allograft fibrosis score based on Banff classification as detailed in Table 2. To exclude potential biases, we determined to what extent serum miRNA levels were confounded with the baseline patient characteristics. Serum miR-21 levels were not different according to patient gender or age (Figure 5A–B). Serum levels of miR-21 in patients with severe fibrosis (IF/TA grade 3) were significantly elevated when compared to other patients (IF/TA grades 0, 1 and 2) (3.0±1.0 vs 1.5±1.2; p<0.001) (Figure 5C). As shown in Figure 5D, circulating miR-21 levels gradually increased with IF/TA fibrosis grade (R = 0.376, p = 0.01). The predictive power of circulating miR-21 levels for the presence of severe kidney fibrosis (IF/TA grade 3) was evaluated by ROC-analysis (Figure 5E). This revealed an area under the curve of 0.891 (95% confidence interval, 0.792–0.989). By contrast, circulating miR-21 levels were not correlated with other Banff criteria related to acute inflammation, chronic vascular or glomerular changes (Figure 6). Subsequently, we assessed the correlation between serum levels of miR-21 with patient renal function. MiR-21 correlated significantly to both estimated glomerular filtration rate (GFR) evaluated by aMDRD formula (regression coefficient R = −0.451, p = 0.003, Figure 5F) and plasmatic creatinine (R = 0.490, p<0.0001, not shown). In a model including IF/TA grade and estimated GFR, multivariate linear regression described independent associations between circulating miR-21 levels and IF/TA score (ß = 0.307, p = 0.03), as well as miR-21 levels and aMDRD (ß = −0.398, p = 0.006). By contrast, no correlation was observed between miR-21 levels and cellular lysis markers (as lactate dehydrogenase, alanine amino transferase and aspartate amino transferase) or C Reactive Protein.

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