543 - Long-Term Profibrotic Transcriptional Changes in Proximal Tubule Epithelia Following Experimental Recurrent Urinary Tract Infection, despite Antibiotic Treatment

Publication Number: 4531.543

Evan A. Rajadhyaksha, Riley Hospital for Children at Indiana University Health, Indianapolis, IN, United States; Jered Myslinski, Indiana University School of Medicine, Indianapolis, IN, United States; Takashi Hato, Indiana University School of Medicine, Indianapolis, IN, United States; David Hains, Indiana University School of Medicine, Indianapolis, IN, United States; Andrew Schwaderer, Indiana University, Indianapolis, IN, United States

Background: Vesicoureteral reflux (VUR) affects 1-3% of children and can increase risk for recurrent episodes of urinary tract infection (UTI), and pyelonephritis. This can lead to kidney injury and scarring with associated functional loss, reflux nephropathy. A mouse model of VUR and UTI has been shown to cause fibrosis and loss of renal functional reserve. Long-term adaptations of the tubular epithelium following UTI have not been assessed.

Objective: Evaluate long-term changes in the kidney following treated recurrent urinary tract infections.

Design/Methods: Female C3H/HeOuJ mice with VUR were given UTI via transurethral inoculation with uropathogenic E. coli. Mice were treated with intraperitoneal cephalosporin starting at 48 hours to mirror when a child may present to the hospital for febrile UTI. A group of control mice remained uninfected. To evaluate the long-term changes in the kidney, mice were allowed 10 weeks following the final intervention cycle to convalesce and establish a new baseline. From three mice in each group, a kidney was homogenized and a single cell suspension prepared for single cell transcriptomics.

Results: Long-term transcriptional changes were observed in the epithelial and immune cells (Figure 1). Of particular interest was upregulation of Nrep/p311 (adjusted p value=1.3x10-69) in proximal tubule epithelia of the UTI group. Upregulation of this gene has been linked in the literature with TGF-β-mediated pro-fibrotic signaling in kidney disease. The resident and infiltrating immune cells also showed differential expression patterns, and T cells (cytotoxic and Th1) and dendritic cells in the UTI mice upregulated pro-fibrotic pathway supporters including Hsp90aa1/ab1 and Hspa8, which may contribute to stabilization of TGF-β receptors. Inhibition of this pathway attenuates renal fibrosis in models of kidney disease.

Conclusion(s): Recurrent UTI causes long-term transcriptional changes in the epithelia and resident immune cells of the kidney. These data demonstrate that recurrent UTI may contribute to a persistent pro-fibrotic state even after “resolution” of the initial injury, and outside of UTI episodes. How this modifies kidney injury risk during and following subsequent UTIs remains to be explored.

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