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Abstract: FR-PO642

Stat3-Driven Urothelial Programming Prevents Urinary Tract Infection (UTI) Chronicity

Session Information

  • Pediatric Nephrology - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1900 Pediatric Nephrology

Authors

  • Gupta, Sudipti, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Cortado, Hanna H., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Kercsmar, Macie M., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Rodriguez, Felipe, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Jackson, Ashley R., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Becknell, Brian, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Spencer, John David, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Ching, Christina B., Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Uropathogenic E. Coli (UPEC) can evade host immunity resulting in urinary tract infection (UTI) chronicity. We have previously demonstrated that STAT3 limits chronic UTI at 7 days. STAT3 controls several cellular processes by regulating gene transcription. Persistent activation of STAT3 has shown to be oncogenic however not much is known about its impact in UTI. We hypothesize that constitutive STAT3 activation has direct effects on urothelial integrity and epithelial immunity.

Methods

6-8 weeks old female FVB/N wild type controls (WT) and constitutively active Stat3 (Stat3C) mice underwent experimental UPEC UTI. Serial bladder tissue and urine were collected up to 7 days post infection (dpi). Cytospins were performed on urine. Immunofluorescent staining was performed on bladders for Keratin 5, pStat3, Ly6G, and Iba-1. TUNEL staining was also performed. A Qiagen RT2 profiler PCR microarray for the IL-6/ STAT3 signaling pathway was also performed on bladders. Results were evaluated by Mann-Whitney U test with p<0.05 being significant.

Results

Stat3C and WT urothelium demonstrated induction of pStat3 after infection, with Stat3C urothelium showing persistent activation at 7 dpi. TUNEL staining demonstrated more signs of cellular apoptosis in the WT compared to Stat3C bladders at 24hpi and 7dpi, with cellular shedding on WT cytospins at corresponding time points. There was an earlier infiltration of neutrophils in the urothelium of WT mice with a later infiltration of macrophages in STAT3C mice. RT2 profile PCR arrays shows altered expression of genes involved in cell cycle regulation, immune cell recruitment, cytokine expression at 24hpi and 7dpi.

Conclusion

Urothelial STAT3 overexpression directly impacts its viability in response to UTI and the recruited inflammatory milieu. Manipulation of this signaling pathway can alter susceptibility to chronic UTI.

Funding

  • NIDDK Support