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Abstract: TH-PO123

Proximal Tubule-Specific Transcriptomic Changes Mediate Sex Differences in Susceptibility to Aristolochic Acid I-Induced AKI in Mice

Session Information

  • AKI: Mechanisms - I
    November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Bahadur, Tej, Stony Brook University Renaissance School of Medicine, Stony Brook, New York, United States
  • Wang, Jiakang, Stony Brook University Renaissance School of Medicine, Stony Brook, New York, United States
  • Bronstein, Robert, Stony Brook University Renaissance School of Medicine, Stony Brook, New York, United States
  • Guo, Yiqing, Stony Brook University Renaissance School of Medicine, Stony Brook, New York, United States
  • Gujarati, Nehaben A., Stony Brook University Renaissance School of Medicine, Stony Brook, New York, United States
  • Revelo Penafiel, Monica Patricia, University of Utah Health, Salt Lake City, Utah, United States
  • Piret, Sian, Stony Brook University Renaissance School of Medicine, Stony Brook, New York, United States
  • Mallipattu, Sandeep K., Stony Brook University Renaissance School of Medicine, Stony Brook, New York, United States
Background

Previous studies have demonstrated the role of sex differences in susceptibility to human and murine models of AKI. However, proximal tubule (PT)-specific transcriptomic changes that mediate these differences have not been previously described. Here, we aim to investigate the sex-specific transcriptomic differences that mediate the susceptibility to AKI in Aristolochic Acid I (AAI)-induced injury model.

Methods

Age-matched male and female mice were administered DMSO (vehicle) or AAI (2mg/kg) every 72 hours for a total of 4 doses. FITC-sinistrin was used to measure GFR. Histological analysis and immunostaining were performed to determine extent of tubular injury and interstitial fibrosis. In addition, single nuclear multiome (RNA and ATAC) sequencing using 10X Genomics to assess changes to the transcriptome and chromatin accessibility.

Results

Immunostaining for AAI DNA adducts showed no significant differences between male and female mice. However, AAI-treated male mice demonstrated an increase in tubular injury and interstitial fibrosis based on H&E, PAS, and immunostaining (Cytokeratin 20) with a decrease in GFR. Single-nuclear multiome data showed all PT segments clustered distinctly between male and female mice (DMSO or AAI) with 2 unique PT clusters only present in the AAI-treated male as compared to all other groups. Key TF motifs were enriched in these 2 unique PT clusters were (cluster 1: Elf4, Ets1, Irf1, Klf2, Stat2) and (cluster 2: Ebf1, Hivep2, Nfkb1, Pax8 and Relb). Pathway enrichment analysis showed enrichment in ribosome, ubiquitin mediated proteolysis and mitophagy-related pathways in these injured PT clusters. In comparison, key TF motifs were enriched in the female PT clusters such as Atp5a1, Ndufa11, Ndufb10 (oxidative phosphorylation) and Aldoa, Dld, Eno1, G6pc, Gapdh (glycolysis and gluconeogenesis). Conversely, key TF motifs enriched in the male PT clusters were Ank3, Atp2b1, Cadm, Cask, Cdh2, Agrn, Cask, Dab1, Epb41, Gphn (splicing factor NOVA regulated synaptic proteins).

Conclusion

To date, this is the first study to demonstrate PT-specific changes to the transcriptome and chromatin accessibility that might mediate sex differences in susceptibility to AKI post-AAI treatment.

Funding

  • NIDDK Support