The Influence of Sex on Early Stage Markers of Kidney Dysfunction in Response to Juvenile Obesity

Bloor, Ian; Sebért, Sylvain; Mahajan, Ravi; Symonds, Michael

doi:10.1161/hypertensionaha.112.195412

Cited by 17 publications

(15 citation statements)

References 43 publications

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“…Prior to 104 weeks of age, there are approximately equal numbers of male-biased and female-biased genes at each age. The increase in the number of genes whose expression is male-biased and the decrease in the number of genes whose expression is female-biased at 104 weeks appear to be explained by male-specific renal fibrosis, inflammation, and immune cell infiltration [14]. Immune response genes ( Tgfb1 , Il-18 , Il-1b , Il-22 , Il-9r , and Il-2rg ;) show male-biased, old-age-dependent increases in expression at 78 and 104 weeks of age.…”

Section: Discussionmentioning

confidence: 99%

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Sex differences in kidney gene expression during the life cycle of F344 rats

et al. 2013

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BackgroundThe kidney functions in key physiological processes to filter blood and regulate blood pressure via key molecular transporters and ion channels. Sex-specific differences have been observed in renal disease incidence and progression, as well as acute kidney injury in response to certain drugs. Although advances have been made in characterizing the molecular components involved in various kidney functions, the molecular mechanisms responsible for sex differences are not well understood. We hypothesized that the basal expression levels of genes involved in various kidney functions throughout the life cycle will influence sex-specific susceptibilities to adverse renal events.MethodsWhole genome microarray gene expression analysis was performed on kidney samples collected from untreated male and female Fischer 344 (F344) rats at eight age groups between 2 and 104 weeks of age.ResultsA combined filtering approach using statistical (ANOVA or pairwise t test, FDR 0.05) and fold-change criteria (>1.5 relative fold change) was used to identify 7,447 unique differentially expressed genes (DEGs). Principal component analysis (PCA) of the 7,447 DEGs revealed sex-related differences in mRNA expression at early (2 weeks), middle (8, 15, and 21 weeks), and late (104 weeks) ages in the rat life cycle. Functional analysis (Ingenuity Pathway Analysis) of these sex-different genes indicated over-representation of specific pathways and networks including renal tubule injury, drug metabolism, and immune cell and inflammatory responses. The mRNAs that code for the qualified urinary protein kidney biomarkers KIM-1, Clu, Tff3, and Lcn2 were also observed to show sex differences.ConclusionsThese data represent one of the most comprehensive in-life time course studies to be published, assessing sex differences in global gene expression in the F344 rat kidney. PCA and Venn analyses reveal specific periods of sexually dimorphic gene expression which are associated with functional categories (xenobiotic metabolism and immune cell and inflammatory responses) of key relevance to acute kidney injury and chronic kidney disease, which may underlie sex-specific susceptibility. Analysis of the basal gene expression patterns of renal genes throughout the life cycle of the rat will improve the use of current and future renal biomarkers and inform our assessments of kidney injury and disease.

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Section: Discussionmentioning

confidence: 99%

“…However, male experimental animals have been shown to be more susceptible to certain metal-induced nephrotoxicity than females [13]. Females also show protection against obesity-related adverse renal events due to decreased inflammatory response [14] compared to males.…”

Section: Introductionmentioning

confidence: 99%

Sex differences in kidney gene expression during the life cycle of F344 rats

et al. 2013

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“…63,64 It is also apparent that the impact of pediatric obesity is strongly influenced by gender, 65 with evidence that females are apparently being protected from the adverse effects of excess adiposity on a range of metabolic processes including inflammatory responses within the kidney. 66 …”

Section: Adipose Tissue Development and Epigenetic Effects On Pediatrmentioning

confidence: 99%

An evolving scientific basis for the prevention and treatment of pediatric obesity

et al. 2014

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The 2013 Pennington Biomedical Research Center’s Scientific Symposium focused on the treatment and management of pediatric obesity and was designed to (i) review recent scientific advances in the prevention, clinical treatment and management of pediatric obesity, (ii) integrate the latest published and unpublished findings and (iii) explore how these advances can be integrated into clinical and public health approaches. The symposium provided an overview of important new advances in the field, which led to several recommendations for incorporating the scientific evidence into practice. The science presented covered a range of topics related to pediatric obesity, including the role of genetic differences, epigenetic events influenced by in utero development, pre-pregnancy maternal obesity status, maternal nutrition and maternal weight gain on developmental programming of adiposity in offspring. Finally, the relative merits of a range of various behavioral approaches targeted at pediatric obesity were covered, together with the specific roles of pharmacotherapy and bariatric surgery in pediatric populations. In summary, pediatric obesity is a very challenging problem that is unprecedented in evolutionary terms; one which has the capacity to negate many of the health benefits that have contributed to the increased longevity observed in the developed world.

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“…Several reports suggest increased susceptibility of females to acute kidney injury and renal toxicity [ 27 - 29 ]. However, male susceptibilities to metal-induced nephrotoxicity and obesity-related adverse kidney effects have been demonstrated in in vivo models [ 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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.

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The Influence of Sex on Early Stage Markers of Kidney Dysfunction in Response to Juvenile Obesity

Cited by 17 publications

References 43 publications

Sex differences in kidney gene expression during the life cycle of F344 rats

Sex differences in kidney gene expression during the life cycle of F344 rats

An evolving scientific basis for the prevention and treatment of pediatric obesity

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

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