Novel roles for urothelium during urinary tract obstruction

摘要 先天性尿路梗阻（UTO）是儿童慢性肾脏疾病的主要原因。有一个 迫切需要采取措施预防梗阻性肾病-由以下原因引起的肾损伤和功能障碍 反对肾脏的尿路上皮衬里经历了大规模的重组，以应对先天性和 获得性UTO，但直到最近这种尿路上皮重塑的意义仍然不清楚。最近 我们小组发表的数据提供了第一个实验证据，表明肾尿路上皮重塑限制了肾功能。 梗阻性肾病的程度。在梗阻期间，肾性尿路上皮通过以下方式保护肾脏免受损伤： 产生由尿斑蛋白组成的顶端斑块。尿路上皮斑块的消耗加速 在先天性UTO的小鼠模型中的实质损失，伴有肾衰竭和死亡。尿路上皮 在单侧输尿管梗阻后，斑块耗竭同样导致实质损失增加， 获得UTO。先天性和后天性UTO模型中的这些数据为我们的中心研究提供了强有力的支持。 这一假说认为，尿路上皮在保护肾脏免受梗阻性肾病中起着重要作用。的 本申请的目的有三方面。首先，我们的目标是确定尿路上皮损伤的作用，作为一个驱动程序， 梗阻性肾病第二，我们将检验尿斑蛋白+细胞的药物增强剂 尿斑蛋白的产生和表达可以在治疗上用来限制阻塞性肾病。最后， 我们将测试尿路上皮蛋白作为小鼠阻塞性肾病诊断生物标志物的潜力， 接受先天性尿路梗阻评估的儿童。该项目的长期目标是改善 通过确定新的诊断、预后和治疗方法来预防UTO患者 进行性慢性肾病

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.