Kidney Week

Abstract: TH-PO651

The Renal Urothelial Plaque Protects the Kidney Following Obstructive Injury

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

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

Birong Li,

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

Ashley R. Jackson,

• Cortado, Hanna H., The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Hanna H. Cortado,

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

Sudipti Gupta,

• 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

The urothelial plaque, comprised of Uroplakin (Upk) proteins, establishes the urine permeability barrier and promotes structural integrity of the urinary tract. The role of the plaque in obstructive nephropathy remains incompletely understood. We tested the hypothesis that the plaque serves a critical role in limiting hydronephrosis and parenchymal injury following obstruction.

Methods

Unilateral ureteral obstruction (UUO) was induced in three week old Upk1b^-/- and wild type (WT) mice. Hydronephrosis was measured by serial ultrasound. Kidneys were analyzed by standard histologic stains and immunohistochemistry (IHC). The plaque was visualized by transmission electron microscopy (TEM). Upk protein levels in total kidney extracts were evaluated by Western blotting. Urothelium from children undergoing pyeloplasty for ureteropelvic junction obstruction (UPJO) was subject to IHC, TEM, and FITC-Dextran permeability studies.

Results

UUO leads to increased Upk protein levels; urothelial stratification and uniform apical Upk expression; and ultrastructural evidence of mature, bladder-like plaque formation in WT mice. In contrast, Upk1b^-/- UUO renal urothelium lacks Upk expression and urothelial plaque, and displays hyperplasia of Krt5/Krt14 cells. Upk1b^-/- UUO kidneys displayed accelerated progression of hydronephrosis and increased parenchymal injury, compared to WT UUO. Urothelium from the renal pelvis and ureteropelvic junction of children with UPJO displayed Krt5/Krt14 hyperplasia, disrupted plaque and tight junctions, and increased permeability to FITC-Dextran, compared to distal urothelium.

Conclusion

Renal urothelium undergoes extensive remodeling following obstructive injury, acquiring the appearance of lower tract urothelium with increased stratification and a mature plaque. The rapid progression of hydronephrosis and parenchymal injury in Upk1b^-/- mice with UUO supports the hypothesis that the plaque serves a key role in protecting the obstructed kidney. Chronic obstructive injury in children with UPJO leads to disruption of the plaque and compromised barrier function. Strategies to augment or stabilize the renal uroplakin plaque may offer a formidable therapeutic approach to preventing acute and chronic obstructive renal injury.

Funding

• NIDDK Support