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Abstract: FR-PO643

The Renal Urothelium Serves Essential Roles in Host Defense and Pathogenesis of Pyelonephritis

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

  • Li, Birong, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Patel, Rishil H., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Cortado, Hanna H., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Gupta, Sudipti, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Ching, Christina B., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Ruiz-Rosado, Juan de Dios, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Wang, Xin, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Jackson, Ashley R., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Becknell, Brian, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Group or Team Name

  • Kidney and Urinary Tract Center.
Background

Uropathogenic Escherichia coli (UPEC) causes over 90% of acute pyelonephritis cases in humans. The urothelial lining of the pelvicalyceal system serves a proposed gatekeeper role in limiting renal parenchymal invasion by UPEC, but the exact mechanisms that account for this function are unclear. In this study we utilized spatial transcriptomics to map host-pathogen interactions within renal urothelium during pyelonephritis.

Methods

We established acute pyelonephritis in female C3H/HeOuJ mice by transurethral inoculation of UPEC strain CFT073. We profiled transcriptional changes in renal pelvic urothelium through spatial transcriptomics at baseline and 7 days post infection (dpi). We validated these changes by QRT-PCR and immunofluorescence microscopy. Upk1b knockout mice were used to investigate the role of the urothelial plaque in the initiation of pyelonephritis.

Results

Spatial transcriptomics identified induction of transcripts with roles in barrier function, leukocyte recruitment, and bactericidal activity in infected renal urothelium. Conversely, transcripts encoding Uroplakin subunits that comprise the urothelial plaque were decreased following infection. Upk1b deletion results in absent urothelial plaque formation. Following transurethral UPEC inoculation, Upk1b-/- mice exhibited reduced renal bacterial burden and decreased neutrophil infiltration, when compared to Upk1b+/+ mice.

Conclusion

The renal pelvis engages multiple antimicrobial mechanisms in response to E. coli pyelonephritis – including the downregulation of urothelial plaque formation, which serves to limit parenchymal invasion by UPEC. This study identifies a foundational role for the urothelial plaque in Gram-negative pyelonephritis and further strengthens the rationale for the development of antimicrobial agents that disrupt UPEC-plaque interactions in preventing pyelonephritis.

Funding

  • NIDDK Support