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.