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Abstract: SA-PO427

Spatiotemporal Patterning of Intrarenal Urothelium During Embryogenesis

Session Information

  • Pediatric Nephrology - II
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1600 Pediatric Nephrology

Authors

  • Hoff, Monica L., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Mosley, Claudia F., The Ohio State University, Columbus, Ohio, United States
  • McHugh, Kirk M., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Becknell, Brian, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Jackson, Ashley R., Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Congenital urinary tract obstruction (UTO) is a leading cause of chronic kidney disease in children. Intrarenal urothelial remodeling occurs prior to parenchymal injury, and formation of a protective uroplakin (Upk) plaque is a key feature of UTO remodeling. Little is known about progenitor-progeny relationships within the renal urothelium during development, precluding efforts to promote adaptive urothelial remodeling during UTO.

Methods

Krt5+, Krt7+, Krt14+, p63+, and Upk+ renal urothelial cells (RUCs) were localized at embryonic days (E)15-E18. EdU (thymidine analogue) was used to identify stage-specific proliferation indices. Krt7+ was used to establish total RUC counts. Renal urothelial thickness was measured at each stage. Krt5CreERT2 and Upk2CreERT2 lines were used to indelibly label Krt5+ or Upk2+ cells and their daughters at E16.

Results

Renal urothelial thickness decreased from E15-E18, and demonstrated heterogeneous expression patterns in renal papilla, fornix and pelvis. Rare, discrete Upk+ RUCs were first observed at E16 and formed a nearly contiguous apical lining by E18. Basal Krt5+ RUCs were first identified at E17. Krt14+ RUCs were robustly expressed at E17-E18. p63+ RUCs were observed in basal renal urothelium beginning at E16, commonly localized to Krt5+ RUCs at E17. Proliferation peaked at E15 and EdU co-localized more commonly to Krt5+ rather than Upk+ RUCs.

Conclusion

Renal urothelium thinned as RUC specification occurred. The identification of Upk+ RUCs at E16 coincides with the initiation of urine production. The appearance of Upk+ prior to Krt5+ RUCs indicates an earlier need for terminally differentiated characteristics, while co-localization of EdU to Krt5+ RUCs suggests a developmental progenitor role. Lineage assays will determine progenitor-progeny relationships and establish model systems to evaluate candidate pathways utilized during UTO remodeling.

Time course of renal urothelial differentiation. * p<0.05; ** p<0.005, ****p<0.0001

Funding

  • NIDDK Support