Abstract: PO1989
Urothelial Injury Triggers Adaptive Remodeling That Limits Congenital and Acquired Obstructive Nephropathy
Session Information
- Pediatric Nephrology: Genetics, Kidney Stones, Quality Improvement, and Case Reports
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Pediatric Nephrology
- 1700 Pediatric Nephrology
Authors
- Li, Birong, Nationwide Children's Hospital, Columbus, Ohio, United States
- Gupta, Sudipti, Nationwide Children's Hospital, Columbus, Ohio, United States
- Ching, Christina B., 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
Group or Team Name
- Nephrology and Urology Research Affinity Group
Background
Congenital urinary tract obstruction (UTO) is the leading cause of chronic kidney disease and end stage renal disease in children. Both congenital and acquired UTO induce renal urothelial cells to remodel and assume a bladder-like morphology, but the mechanisms and significance of these changes remain unclear. We hypothesize that urothelial remodeling occurs as a consequence of injury to Uroplakin (UPK) expressing cells and serves to attenuate obstructive nephropathy.
Methods
Urothelial injury markers were measured by ELISA in children undergoing pyeloplasty for congenital ureteropelvic junction obstruction (UPJO) versus non-obstructed controls. Male and female mice underwent acquired UPJO via unilateral ureteral obstruction (UUO). The fate of Upk+ cells during UUO was traced through the use of Cre/LoxP mapping. The impact of Upk plaque loss on the kidney’s response to UUO was assessed through the use of Upk1b-/- mice. The effects of Upk+ cell depletion during UUO were gauged by administering diphtheria toxin (DT) to Upk2iCre(+); Rosa26DTR/+mice.
Results
Urine from children with congenital UPJO contains elevated urothelial injury markers – including KRT14, UPK2, and KRT20 – compared to unobstructed controls. Mice with UUO exhibit urothelial apoptosis and increased mRNA and protein expression of urothelial injury markers. Lineage analysis of Upk+ cells demonstrates that UUO triggers a sequence of Upk protein downregulation, proliferation, and elaboration of a bladder-like urothelial plaque. When this process is disrupted via Upk1b deletion or depletion of Upk+ cells, UUO results in augmented tubular injury and interstitial fibrosis.
Conclusion
Urothelial injury is a conserved response to UTO and initiates a series of events that culminate in protective, bladder-like remodeling. The resulting expansion of Upk+ cells and production of urothelial plaque represent an essential adaptation to limit renal parenchymal injury during UTO.
Funding
- NIDDK Support