Abstract: SA-PO609
The PPARγ Signaling Pathway Regulates Urothelial Adaptation During Urinary Tract Obstruction in Mice
Session Information
- Pediatric Nephrology - II
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Pediatric Nephrology
- 1800 Pediatric Nephrology
Authors
- Miehls, Alexa, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Grounds, Kelly, 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
- Kercsmar, Macie M., 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
- Jackson, Ashley R., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
Background
Urinary Tract Obstruction (UTO) is a leading cause of chronic kidney disease in children. No treatments can prevent kidney injury, but heterogeneous outcomes implicate unknown protective adaptations. We previously reported that mice with UTO adapt a bladder-like urothelial lining - characterized by the acquisition of terminally differentiated plaque producing uroplakin-expressing cells (UPK-UCs) along the renal urothelium. Depletion of UPK-UCs or the urothelial plaque accelerate UTO-induced structural and functional injury, suggesting that formation of UPK-UCs is protective. The adult tissue repair progenitor, and the molecular program that governs UTO-induced renal urothelium remodeling is unknown. In the bladder, UPK-UCs function as tissue repair progenitors, and the PPARγ signaling pathway drives urothelial differentiation. Thus, we hypothesized that UPK-UCs to activate PPARγ signaling during UTO-induced renal urothelium remodeling.
Methods
UTO was modeled using unilateral ureteral obstruction. Lineage analysis was performed using Upk2CreERT2;R26tdT mice. Immunofluorescent localization was used to profile the PPARγ signaling pathway during experimental UTO. We used Upk2CreERT2;R26DTR mice to deplete UPK-UCs during UTO. We conditionally disrupted PPARγ signaling using UpkCreERT2;Ppargfl/fl (Pparg-cKO), and Ppargfl/fl mice during UTO.
Results
Lineage analysis experiments showed that adult UPK-UCs were the major contributor to UTO-induced renal urothelium remodeling. At post-operative day 7 and 10, renal urothelium expressed de novo PPARγ and FABP4 (a direct transcriptional target of PPARγ signaling), which co-localized to UPK-UCs. In mice where UPK-UCs were genetically depleted, we observed diminished PPARγ and FABP4 during UTO. Finally, we found that Pparg-cKOs had fewer UPK-UCs during UTO than Ppargfl/fl mice.
Conclusion
Our results indicate that UTO-induced urothelial remodeling is achieved through activation of the PPARγ signaling pathway in UPK-UCs. Future studies will investigate the impact of Pparg-cKO and PPARγ gain of function experiments on kidney injury/function during UTO. Altogether, our findings advance our understanding of renal adaptation to UTO, and reveal a potential mechanism with therapeutic utility for mitigating obstructive kidney disease in children.
Funding
- NIDDK Support