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Abstract: FR-PO644

Gain- and Loss-of-Function Approaches Substantiate Roles for Ribonuclease 6 in 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

  • Cortado, Hanna H., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Kercsmar, Macie M., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Li, Birong, 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
  • Wang, Xin, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Spencer, John David, 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
  • 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

Acute pyelonephritis (APN) episodes can result in urosepsis, acute kidney injury, and renal scarring. Identifying mechanisms of host defense against APN is a priority to mitigate these sequelae, particularly in an era of mounting antibiotic resistance. Ribonuclease 6 (RNase 6) is a cationic protein with potent bactericidal activity toward uropathogenic Escherichia coli (UPEC). We took complementary approaches to examine roles for RNase 6 in experimental APN.

Methods

We utilized a novel Rnase6EGFP/+ knockin allele to identify the cellular sources of RNase 6 and the impact of its deficiency on APN susceptibility in mice. As a complementary approach we generated human RNASE6 transgenic mice. Flow cytometry, immunofluorescence microscopy, and scRNAseq identified cellular sources of RNase6 within the kidney. The role of RNase 6 in intracellular UPEC killing was identified in a gentamicin protection assay using bone marrow derived macrophages (BMDM).

Results

Mouse and human RNase 6 are expressed by resident mononuclear phagocytes and circulating monocytes that are recruited to the infected kidney during APN. Rnase6 deficient mice are more susceptible to APN, whereas RNASE6 transgenic mice exhibit reduced renal UPEC burden. Rnase6 deficiency is associated with increased intramacrophage UPEC survival, while human RNASE6 transgenic macrophages are more adept at killing phagocytosed UPEC.

Conclusion

RNase 6 is an essential antimicrobial protein within the renal mononuclear phagocyte system that promotes UPEC clearance during APN.

Funding

  • NIDDK Support