Male Mice Have Increased Expression of Renal Genes Linked to Kidney Disease Compared with Gene Expression in Female Mice

Background: Men are at increased risk of reaching kidney failure sooner than women, even though less men have chronic kidney disease (CKD) compared to women. Gene expression profiles have linked inflammaiton and fibrosis as contributors to CKD on a molecular level. Kidney function is influenced by circadian rhythms, therefore, consideration of the time of day is warranted. Both humans and mice are diurnal, however, mice are nocturnal and are active during the night. We hypothesized that male young adult mice will have up-regulated expression of genes that are linked to CKD progression compared to female mice. Methods: We used six-month-old male and female control mice on a C57BL/6 background. Kidneys were harvested at zeitgeber time (ZT) 0 or ZT12, at the beginning of the inactive and active periods for mice. RNA was isolated from the renal medulla and prepared for RNA sequencing (5-9 pooled samples for males, 4-8 for females). Differential gene expression was analyzed using DESeq2 (abs(log2(FC)) ≥ 1.0 and FDR-corrected P-value ≤ 0.05). Qiagen ingenuity pathway analysis was performed. Results: At ZT0, there were 469 differentially expressed genes between males and females. There were 525 differentially expressed genes at ZT12. Interestingly, genes linked to kidney damage are down-regulated in females at both time points compared to males. The kidney injury molecule, Havcr1, was down-regulated in females compared to males only at ZT0 (log2(FC)=-2.4; P=0.04). However, renal inflammation pathways were up-regulated in females. Cxcr4 was one of the contributors to this finding, which is a gene that promotes infiltration of inflammatory cell to the inflammation site. Cxcr4 was only found to be up-regulated in female mice at ZT0 (log2(FC)=1.3; P=0.01). The anti-aging protein Klotho (Kl) was surprisingly down-regulated in females compared to age-matched males at both time points (log2(FC)=1-1.2; P<0.001). Conclusion: In conclusion, female mice have down-regulated expression of genes that are linked to the development of CKD compared to males. More of these CKD-related genes were found to be differentially expressed at the beginning of the inactive period vs. active period of the mice. There is evidence that females have up-regulation of genes that promotoe renal inflammation. This finding is interesting as women are more likely to develop immune-related kidney diseases compared to men. Funding: NIDDK Support