Abstract: TH-PO1089
Kidney Scarring After Pyelonephritis Is Associated with Alternative Splicing Reprogramming
Session Information
- Pathology and Lab Medicine
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1700 Pathology and Lab Medicine
Authors
- 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
- Li, Birong, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Li, Qiushi, 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
- Wang, Xin, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
Group or Team Name
- Kidney and Urinary Tract Center
Background
Alternative splicing (AS) is a post-transcriptional regulatory mechanism that expands proteomic diversity through selective exon usage, yet its contribution to tissue injury associated with pyelonephritis (PN) remains poorly defined. Studies on renal scarring (RS) have classically focused on differential gene and protein expression while largely overlooking the role of AS on fibrosis progression. In a preclinical model of PN, antibiotic-mediated clearance of uropathogens fails to prevent RS, suggesting host-driven regulatory programs may contribute to fibrotic injury. Given these observations, we aimed to characterize the RNA splicing changes associated with RS following PN.
Methods
Bulk RNA-sequencing was performed on female C3H/HeOuJ mouse kidneys following infection with uropathogenic Escherichia coli (UPEC) and daily ceftriaxone treatment from 7-16 days post-infection (dpi). Kidneys were analyzed at 44 dpi to assess AS changes in mild, moderate, and severely scarred tissue (n=3-5/group). Differential AS events (FDR<0.05, |ΔPSI|>0.1) were identified and integrated with our spatial and single-cell transcriptomic PN atlases spanning sham to 28 dpi. Spatial molecular imaging from chronically infected patient kidneys (n=4) was utilized for localization of differentially spliced genes.
Results
Differential splicing analysis revealed a progressive expansion of significant splicing events, with 277, 441, and 994 events detected in mild, moderate, and severe RS, respectively. Splicing-associated genes were enriched in JNK signaling, cell-matrix adhesion, and focal adhesion assembly pathways. These genes were preferentially active in areas of inflammation, specifically in T and B lymphocytes, macrophages, fibroblasts, and proximal tubule S1/S2 cells after 7 dpi (P<0.05). Exon skipping in Ptk2 increased with scarring severity, while Tpm1 exhibited multi-event splicing dysregulation. In patient kidneys, PTK2 and TPM1 transcripts were present within inflamed tubules and fibrotic regions, paralleling the murine pattern.
Conclusion
Pyelonephritis induces severity-scaled alternative splicing of cell signaling and adhesion pathways that persist after infection clearance and localize to fibrotic niches. These splicing programs represent key host regulatory mechanisms in renal scarring and may serve as biomarkers or therapeutic targets to mitigate disease progression.