Abstract: FR-PO874
Multi-Omics of Sex-Based Differences in Nephrotoxic Serum Nephritis
Session Information
- Women's Health and Kidney Diseases
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Women's Health and Kidney Diseases
- 2200 Women's Health and Kidney Diseases
Authors
- Garcia, Valerie, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Wright, Matthew, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Liu, Esther, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Campbell, Andra, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Kearney, Andrew O., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Lin, Jennie, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background
Sex-based differences have been observed in the incidence and clinical course of acute kidney injury as well as chronic kidney disease. Compared to males, female patients are more protected from kidney injury and disease progression. Prior studies have identified sexual dimorphism in kidney development and ischemic response, but the mechanisms by which inflammatory stimuli contribute to kidney sex-based differences have not been fully elucidated.
Methods
To examine these differences, we induced nephrotoxic serum (NTS) nephritis in female and male C57BL/6 mice of either 8-12 weeks or 18 months of age. Changes in urine and serum markers were measured, and differences in fibrosis were quantified by Sirius Red staining in kidneys harvested on Day 10. Multi-omics data from matched single nucleus RNA-seq (snRNA-seq) and single nucleus ATAC-seq (snATAC-seq) were generated from those kidneys, with 66,430 nuclei examined.
Results
On Days 4, 7, and 10 after NTS injection, young male mice had significantly higher urinary albumin to creatinine ratio than young females (p<0.01), while no differences in albuminuria were seen in aged males vs. females. Although no significant sex-based differences in serum creatinine or renal fibrosis were observed, on a molecular level snRNA-seq revealed major NTS-induced differences in metabolic programs in young male vs. female proximal tubule segments and endothelial cells, and surprisingly few transcriptomic changes in immune cells. Most differentially accessible chromatin regions (DARs) were found in the S3 segment of the proximal tubule with notable motif enrichment for Hnf4a, while DARs in endothelial cells were enriched for Stat3/5 binding motifs. Overall correlation between DARs and differential gene expression across cell populations was 0.54. Despite loss of female renoprotection in aged females, differentially accessible chromatin regions in young females were not enriched in motifs containing estrogen responsive elements, suggesting that cis-regulation by ESR1 is not the direct driver of sex-based differences in NTS nephritis.
Conclusion
Sexual dimorphism in NTS nephritis is characterized by more severe albuminuria in young male mice, likely due to sex-based differences in metabolic pathways in different cell populations rather than direct cis-regulatory function of estrogen receptor binding activity.
Funding
- NIDDK Support