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Kidney Week

Abstract: SA-PO429

Terminal Differentiation of the Intrarenal Urothelium Attenuates Kidney Injury During Congenital and Acquired Urinary Tract Obstruction

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

  • Jackson, Ashley R., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Li, Birong, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Cohen, Shira H., The Research Institute at Nationwide Children''s Hospital, Columbus, Ohio, United States
  • Gupta, Sudipti, Nationwide Childrens Hospital , Columbus, Ohio, United States
  • Ching, Christina B., Nationwide Children''s Hospital, 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
Background

Congenital urinary tract obstruction (UTO) is the leading cause of chronic kidney disease and end stage renal disease in children. Despite timely detection and surgical correction of the primary obstructive lesion, outcomes vary widely with regard to CKD progression. We hypothesized that remodeling of the intrarenal urothelium confers a protective adaptation during congenital and acquired UTO, by terminal differentiation and elaboration of a highly compliant uroplakin (Upk) plaque.

Methods

The Upk plaque was destabilized in a congenital model of functional lower UTO by generating Mgb-/-;Upk1b-/- mice. As an acute UTO model, unilateral ureteral obstruction (UUO) was induced in young adult Upk1b-/- and wild type (WT) mice. Alternatively, diphtheria toxin (DT)-mediated depletion of Upk(+) cells was induced following UUO. Urine UPK2 and UPK3A levels were measured by ELISA in children undergoing pyeloplasty for ureteropelvic junction obstruction (UPJO) versus nonobstructed controls.

Results

During congenital and acquired UTO, progressive hydronephrosis triggers reorganization of the intrarenal urothelium, which elaborates a continuous Upk plaque. Upk1b-/-;Mgb-/- mice experience accelerated onset of bilateral hydronephrosis with severe (>67%) parenchymal loss, leading to renal failure and mortality in adolescence. Upk1b deletion or depletion of Upk+ cells accelerate renal parenchymal loss following ureteral ligation, attesting to a conserved, stabilizing role for Upk plaque deposition in the acutely obstructed kidney. Lineage analysis demonstrates that UUO triggers a sequence of Upk plaque loss, proliferation, and reacquisition of the Upk plaque by Upk+ cells. Children with UPJO manifest higher urinary UPK protein levels than unobstructed controls.

Conclusion

These complementary experiments provide the first evidence that the Upk plaque confers an essential, protective adaptation to preserve renal parenchymal integrity during congenital and acquired urinary tract obstruction.

Funding

  • NIDDK Support