Kidney Week

Abstract: TH-PO650

The Uroplakin Plaque Promotes Renal Structural Integrity During Congenital and Acquired Urinary Tract Obstruction

Session Information

• Pediatric Nephrology
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Developmental Biology and Inherited Kidney Diseases

• 403 Pediatric Nephrology

Authors

• Jackson, Ashley R., The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Ashley R. Jackson,

• Li, Birong, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Birong Li,

• Gupta, Sudipti, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Sudipti Gupta,

• Cohen, Shira H, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Shira H Cohen,

• Millner, Rachel, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Rachel Millner,

• Ching, Christina B., The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Christina B. Ching,

• McHugh, Kirk M., The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Kirk M. McHugh,

• Becknell, Brian, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Brian Becknell,

Background

Congenital urinary tract obstruction (UTO) is the leading cause of chronic kidney disease and end stage renal disease in children. Yet many children with congenital ureteropelvic junction obstruction (UPJO) can be managed nonoperatively, with spontaneous improvement or resolution of hydronephrosis on postnatal imaging. This implies the existence of renal adaptations during UTO that preserve parenchymal integrity and function. We hypothesized that uroplakin (Upk) expression by renal urothelial cells initiates a protective adaptation during congenital and acquired UTO, serving as a gatekeeper to progressive renal injury.

Methods

The Upk plaque was destabilized in a congenital model of functional lower UTO by generating Mgb^-/-;Upk1b^-/- mice. Diphtheria toxin (DT)-mediated depletion of Upk(+) cells was induced following unilateral ureteral obstruction (UUO) in Upk2^CreERT2/+;R26^DTR/+ mice (acute UTO model). Urine UPK2 and UPK3A levels were measured by ELISA in children undergoing pyeloplasty for UPJO versus nonobstructed controls.

Results

In Mgb^-/- mice with congenital hydronephrosis, the renal urothelium acquires a bladder-like cellular composition and ultrastructure. The extent of hydronephrosis positively correlates with Upk mRNA content in Mgb^-/- kidneys. Likewise, urinary UPK3A and UPK2 levels increase in children with UPJO, when compared to nonobstructed controls. Mgb^-/-; Upk1b^-/- mice display disrupted renal urothelial ultrastructure; rapid onset of bilateral hydronephrosis; and adolescent mortality due to renal failure, compared to single gene deficient or wild type control mice. DT-depletion of Upk(+) cells in Upk2^CreERT2/+;R26^DTR/+ mice accelerates the progression of hydronephrosis following UUO. Absence of the Upk plaque leads to increased interstitial fibrosis in both congenital and acute UTO models, respectively, compared to Upk intact controls.

Conclusion

These studies provide the first experimental evidence that the renal Upk plaque confers an essential, protective adaptation during congenital and acquired UTO. Conversely, loss of the Upk plaque leaves the kidney vulnerable to obstructive hydronephrosis and may identify patients in need of surveillance or more immediate surgical intervention for renal deterioration.

Funding

• NIDDK Support