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Kidney Week

Abstract: FR-PO1099

Context-Specific Cellular Mechanisms of Urothelial Development and Repair in the Kidney

Session Information

Category: Pediatric Nephrology

  • 1700 Pediatric Nephrology

Authors

  • Jackson, Ashley R., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Hoff, Monica L., The Ohio State University College of Medicine, Columbus, Ohio, United States
  • Li, Birong, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Ching, Christina B., Nationwide Children's Hospital, Columbus, Ohio, United States
  • McHugh, Kirk M., The Ohio State University College of Medicine, Columbus, Ohio, United States
  • Becknell, Brian, Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Congenital urinary tract obstruction (UTO) is a leading cause of pediatric chronic kidney disease and end stage renal disease. The renal urothelium is the kidney’s anatomic front line of defense during UTO, and represents an understudied but novel therapeutic target. Renal urothelium contains two mutually exclusive, Krt5+ and Upk+ renal urothelial cell (RUC) populations. UTO triggers an iterative RUC remodeling sequence that culminates in the formation of bladder-like Upk+ apical plaque producing RUCs, which attenuate UTO injury. The ontology of Upk+ RUCs is unknown, stalling efforts to therapeutically promote protective renal urothelial remodeling.

Methods

In this study, we performed genetic fate mapping to determine whether Upk+ RUC arise through self-renewal or via differentiation from Krt5+ RUC. We mapped the fate of Upk+ and Krt5+ RUC lineages in Upk2CreERT2/+;R26tdT/+and Krt5CreERT2/+;R26tdT/+mice, and performed immunofluorescent assays to mark Krt5, Krt14, p63, foxa1, Upk, Krt20, tdT-expressing and proliferating cells across development. Unilateral ureteral obstruction was used to trigger UTO.

Results

Renal urothelium develops at embryonic day 17, and temporal waves of Upk and Krt5 expression are observed through adulthood. Krt5+ RUCs commonly express Krt14 and p63 and are the primary proliferative RUC. Adult Upk+ RUCs derive from embryonic and neonatal Krt5+ RUCs. Paralleling a proliferative decline, Krt5+ RUCs lose progenitor capacity by postnatal day 14. In a temporally restricted manner, UTO triggers formerly lineage restricted Krt5+ RUCs to regain progenitor capacity and form bladder-like Upk+ RUCs. In addition, adult Upk+ RUCs possess the ability to lose Upk protein expression, proliferate, and give rise to daughter Upk+ RUCs that reacquire Upk protein synthesis.

Conclusion

This study is the first to establish the temporal manner in which the embryonic and postnatal renal urothelium is patterned, and demonstrates the contexts during which Upk+ RUCs arise via self-renewal versus differentiation from Krt5+ progenitors. Identification of the context-specific mechanisms governing progenitor plasticity or restriction have broad implications for urothelial development, repair and therapeutic manipulation.

Funding

  • NIDDK Support