Novel roles for urothelium during urinary tract obstruction

ABSTRACT
Congenital urinary tract obstruction (UTO) is the leading cause of chronic kidney disease in children. There is a
critical need for measures to prevent obstructive nephropathy – the renal injury and dysfunction that result from
UTO. The urothelial lining of the kidney undergoes massive reorganization in response to congenital and
acquired UTO, but until recently the significance of this urothelial remodeling has remained unclear. Recently
published data from our group provide the first experimental evidence that renal urothelial remodeling limits the
extent of obstructive nephropathy. During obstruction, the renal urothelium protects the kidney from injury by
producing an apical plaque composed of Uroplakin proteins. Depletion of the urothelial plaque accelerates
parenchymal loss in a mouse model of congenital UTO, accompanied by renal failure and death. Urothelial
plaque depletion likewise results in increased parenchymal loss following unilateral ureteral obstruction, a model
of acquired UTO. These data in congenital and acquired UTO models provide strong support for our central
hypothesis that the urothelium plays an essential role in protecting the kidney from obstructive nephropathy. The
objectives of this application are three-fold. First, we aim to define the role of urothelial injury as a driver of
obstructive nephropathy. Second, we will test the hypothesis that pharmaceutical enhancers of Uroplakin+ cell
generation and Uroplakin expression can be harnessed therapeutically to limit obstructive nephropathy. Last,
we will test the potential of urothelial proteins as diagnostic biomarkers of obstructive nephropathy in mice and
in children undergoing evaluation for congenital UTO. The long-term objective of this project is to improve the
care of patients with UTO by identifying novel diagnostic, prognostic, and therapeutic approaches to prevent
progressive chronic kidney disease.

Grant Number: 5R01DK125469-05
NIH Institute/Center: NIH
Principal Investigator: Brian Becknell