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Age and sex differences in kidney microRNA expression during the life span of F344 rats.

Kwekel JC, Vijay V, Desai VG, Moland CL, Fuscoe JC - Biol Sex Differ (2015)

Bottom Line: Differential expression was determined using filtering criteria of ≥1.5 fold change and ANOVA or pairwise t-test (FDR <5%) to determine significant age and sex effects, respectively.Three hundred eleven miRNAs were found to be expressed in at least one age and sex.Principal component analysis revealed age effects predominated over sex effects, with 2-week miRNA expression being much different from other ages.

View Article: PubMed Central - PubMed

Affiliation: Division of Systems Biology, Personalized Medicine Branch, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079 USA.

ABSTRACT

Background: Growing evidence suggests that epigenetic mechanisms of gene regulation may play a role in susceptibilities to specific toxicities and adverse drug reactions. MiRNAs in particular have been shown to be important regulators in cancer and other diseases and show promise as predictive biomarkers for diagnosis and prognosis. In this study, we characterized the global kidney miRNA expression profile in untreated male and female F344 rats throughout the life span. These findings were correlated with sex-specific susceptibilities to adverse renal events, such as male-biased renal fibrosis and inflammation in old age.

Methods: Kidney miRNA expression was examined in F344 rats at 2, 5, 6, 8, 15, 21, 78, and 104 weeks of age in both sexes using Agilent miRNA microarrays. Differential expression was determined using filtering criteria of ≥1.5 fold change and ANOVA or pairwise t-test (FDR <5%) to determine significant age and sex effects, respectively. Pathway analysis software was used to investigate the possible roles of these target genes in age- and sex-specific differences.

Results: Three hundred eleven miRNAs were found to be expressed in at least one age and sex. Filtering criteria revealed 174 differentially expressed miRNAs in the kidney; 173 and 34 miRNAs exhibiting age and sex effects, respectively. Principal component analysis revealed age effects predominated over sex effects, with 2-week miRNA expression being much different from other ages. No significant sexually dimorphic miRNA expression was observed from 5 to 8 weeks, while the most differential expression (13 miRNAs) was observed at 21 weeks. Potential target genes of these differentially expressed miRNAs were identified.

Conclusions: The expression of 56% of detected renal miRNAs was found to vary significantly with age and/or sex during the life span of F344 rats. Pathway analysis suggested that 2-week-expressed miRNAs may be related to organ and cellular development and proliferation pathways. Male-biased miRNA expression at older ages correlated with male-biased renal fibrosis and mononuclear cell infiltration. These miRNAs showed high representation in renal inflammation and nephritis pathways, and included miR-214, miR-130b, miR-150, miR-223, miR-142-5p, miR-185, and miR-296*. Analysis of kidney miRNA expression throughout the rat life span will improve the use of current and future renal biomarkers and inform our assessments of kidney injury and disease.

No MeSH data available.


Related in: MedlinePlus

Differentially expressed miRNAs (174 miRNAs) were clustered in 10 k-means clusters. Ten clusters were chosen as an estimate of the number of large-scale expression patterns within the life span. As most miRNA expression changes are very subtle, miRNAs generally clustered according to normalized expression level.
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Fig3: Differentially expressed miRNAs (174 miRNAs) were clustered in 10 k-means clusters. Ten clusters were chosen as an estimate of the number of large-scale expression patterns within the life span. As most miRNA expression changes are very subtle, miRNAs generally clustered according to normalized expression level.

Mentions: To visualize the expression patterns of individual DEMs, k-means clustering was utilized to group miRNAs into common patterns (Figure 3). The number of k-means clusters was set at 10 as a modest estimation of the diversity present within the data. DEMs tended to cluster according to normalized intensity level; highly expressed miRNAs clustered with other highly expressed miRNAs and lowly expressed miRNAs with other low expressers. This clustering behavior likely occurred due to the relative stability of expression of all miRNAs throughout the life span. MiRNAs that are expressed at a certain level at an early age tend to maintain that expression level throughout the life span, in both sexes. Members of the let-7 family of miRNAs (7a, 7c, 7f, and 7b) exhibit the highest expression levels throughout the life span. Slight differences in expression are evident at 2 weeks for some miRNAs, especially those in clusters 4, 6, and 7.Figure 3


Age and sex differences in kidney microRNA expression during the life span of F344 rats.

Kwekel JC, Vijay V, Desai VG, Moland CL, Fuscoe JC - Biol Sex Differ (2015)

Differentially expressed miRNAs (174 miRNAs) were clustered in 10 k-means clusters. Ten clusters were chosen as an estimate of the number of large-scale expression patterns within the life span. As most miRNA expression changes are very subtle, miRNAs generally clustered according to normalized expression level.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4316605&req=5

Fig3: Differentially expressed miRNAs (174 miRNAs) were clustered in 10 k-means clusters. Ten clusters were chosen as an estimate of the number of large-scale expression patterns within the life span. As most miRNA expression changes are very subtle, miRNAs generally clustered according to normalized expression level.
Mentions: To visualize the expression patterns of individual DEMs, k-means clustering was utilized to group miRNAs into common patterns (Figure 3). The number of k-means clusters was set at 10 as a modest estimation of the diversity present within the data. DEMs tended to cluster according to normalized intensity level; highly expressed miRNAs clustered with other highly expressed miRNAs and lowly expressed miRNAs with other low expressers. This clustering behavior likely occurred due to the relative stability of expression of all miRNAs throughout the life span. MiRNAs that are expressed at a certain level at an early age tend to maintain that expression level throughout the life span, in both sexes. Members of the let-7 family of miRNAs (7a, 7c, 7f, and 7b) exhibit the highest expression levels throughout the life span. Slight differences in expression are evident at 2 weeks for some miRNAs, especially those in clusters 4, 6, and 7.Figure 3

Bottom Line: Differential expression was determined using filtering criteria of ≥1.5 fold change and ANOVA or pairwise t-test (FDR <5%) to determine significant age and sex effects, respectively.Three hundred eleven miRNAs were found to be expressed in at least one age and sex.Principal component analysis revealed age effects predominated over sex effects, with 2-week miRNA expression being much different from other ages.

View Article: PubMed Central - PubMed

Affiliation: Division of Systems Biology, Personalized Medicine Branch, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079 USA.

ABSTRACT

Background: Growing evidence suggests that epigenetic mechanisms of gene regulation may play a role in susceptibilities to specific toxicities and adverse drug reactions. MiRNAs in particular have been shown to be important regulators in cancer and other diseases and show promise as predictive biomarkers for diagnosis and prognosis. In this study, we characterized the global kidney miRNA expression profile in untreated male and female F344 rats throughout the life span. These findings were correlated with sex-specific susceptibilities to adverse renal events, such as male-biased renal fibrosis and inflammation in old age.

Methods: Kidney miRNA expression was examined in F344 rats at 2, 5, 6, 8, 15, 21, 78, and 104 weeks of age in both sexes using Agilent miRNA microarrays. Differential expression was determined using filtering criteria of ≥1.5 fold change and ANOVA or pairwise t-test (FDR <5%) to determine significant age and sex effects, respectively. Pathway analysis software was used to investigate the possible roles of these target genes in age- and sex-specific differences.

Results: Three hundred eleven miRNAs were found to be expressed in at least one age and sex. Filtering criteria revealed 174 differentially expressed miRNAs in the kidney; 173 and 34 miRNAs exhibiting age and sex effects, respectively. Principal component analysis revealed age effects predominated over sex effects, with 2-week miRNA expression being much different from other ages. No significant sexually dimorphic miRNA expression was observed from 5 to 8 weeks, while the most differential expression (13 miRNAs) was observed at 21 weeks. Potential target genes of these differentially expressed miRNAs were identified.

Conclusions: The expression of 56% of detected renal miRNAs was found to vary significantly with age and/or sex during the life span of F344 rats. Pathway analysis suggested that 2-week-expressed miRNAs may be related to organ and cellular development and proliferation pathways. Male-biased miRNA expression at older ages correlated with male-biased renal fibrosis and mononuclear cell infiltration. These miRNAs showed high representation in renal inflammation and nephritis pathways, and included miR-214, miR-130b, miR-150, miR-223, miR-142-5p, miR-185, and miR-296*. Analysis of kidney miRNA expression throughout the rat life span will improve the use of current and future renal biomarkers and inform our assessments of kidney injury and disease.

No MeSH data available.


Related in: MedlinePlus