Abstract
BackgroundGrowing 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.MethodsKidney 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.ResultsThree 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-014-0019-1) contains supplementary material, which is available to authorized users.
Highlights
Growing evidence suggests that epigenetic mechanisms of gene regulation may play a role in susceptibilities to specific toxicities and adverse drug reactions
We investigated whether epigenetic mechanisms of gene regulation, such as changes in miRNA expression, are present in the kidney that may underlie age- and sex-specific susceptibilities to adverse renal events
Sex- and age-associated renal histopathology Histological examination of kidney tissues at 52, 78, and 104 weeks of age revealed moderate to marked mononuclear cell infiltration in males compared to only mild to moderate infiltration in females (Table 1 and Additional file 1)
Summary
Growing evidence suggests that epigenetic mechanisms of gene regulation may play a role in susceptibilities to specific toxicities and adverse drug reactions. Growing evidence suggests that epigenetic mechanisms of gene regulation may play a role in susceptibilities to specific renal diseases, toxicities, and adverse drug reactions. Complete oblation of miRNA function by deleting the miRNA processing gene Dicer in mouse podocytes reveals deficient podocyte homeostasis, reduced nephrogenesis, and other glomerular abnormalities that lead to lethality in young mice [6] This suggests crucial roles of miRNA regulation in podocyte function that positively impact total kidney function. Further evidence pointed to miR-151’s protective effects being mediated via targeted suppression of c-Fos, a key regulator of apoptotic signaling [8] These protective effects suggest miRNAs play a role in mediating key kidney functions; blocking miRNA function via Dicer knockout in proximal tubule cells showed protective effects against acute kidney injury [9]. Mechanisms for both beneficial and deleterious roles of miRNA function in the kidney remain to be understood fully
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