Sex specific differences in renal disease incidence and progression as well as in drug-induced nephrotoxicity are well established, but the molecular mechanisms responsible for these differences are not very well understood. James Fuscoe and colleagues from the National Center for Toxicological Research of the US Food and Drug Administration, USA sought to address this issue by analysing the expression of genes in the kidneys of male and female rats during post-natal development. The results of their extensive study are published in the journal Biology of Sex Differences.
The researchers performed whole genome microarray analysis on kidney samples collected from male and female Fischer 344 rats at eight age groups between two and 104 weeks of age. A total of 7,447 genes were found to be differentially expressed by age or sex in the kidney, and further analysis revealed three distinct patterns.
First, at two weeks, animals exhibited 130 genes with a male or female bias, however of these genes only 50 remained differentially expressed between the sexes later in development during weeks two to five. Second, the highest numbers of sex-biased genes were observed in mice aged 8, 15 and 21 weeks when compared to the other ages. Using Venn analysis, the authors identified 114 genes that were common to all three of these age groups; of these 69 showed a female bias and 45 showed a male bias. Looking more closely at these sex-biased genes the authors found very different biology was reflected between the sexes, with female-biased genes mostly involved in drug metabolism, renal tubule injury and lipid metabolism, and male-biased genes having a role in steroid metabolism and cholestasis pathways.
The third pattern detected was at 104 weeks, when the majority of the sex-biased genes showed a male-biased pattern of expression. Functional analysis of the male-biased genes revealed an over-representation of immune and inflammation response genes. Subsequent histological analysis confirmed increased renal fibrosis in males compared with females, which results from an increased immune response. The authors speculated that the higher expression of these genes in males compared to females may explain why women have a reduced risk of developing age-related fibrosis and inflammation.
One of the most interesting findings of the study pertains to six gene products that have been approved by the US Food and Drug Administration for use in preclinical monitoring of disease- and drug-induced nephrotoxicity. Fuscoe and colleagues found that the expression levels of genes encoding five of the six approved biomarkers exhibited a marked sex difference, which could have an effect on their use and utility. For example, the gene encoding kidney injury molecule-1 exhibited a 23-fold difference at eight weeks, which is also the most common age for toxicity evaluations in rats.
This comprehensive analysis of sex-related changes in gene expression during the rat life cycle not only adds to the current understanding of kidney function, but also has major implications for the current use and future development of biomarkers for kidney injury.