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脏损伤和功能障碍 乌托。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，表明肾上皮重塑限制了 梗阻性肾病的程度。在梗阻期间，肾上皮通过以下方式保护肾脏免受损伤 产生由尿路蛋白组成的心尖斑块。尿路上皮斑块的消耗加速 先天性输尿管梗阻小鼠模型的实质丢失，并伴有肾功能衰竭和死亡。尿路上皮 斑块耗竭同样会导致单侧输尿管梗阻后实质丢失的增加。 收购的UTO。先天性和获得性UTO模型中的这些数据为我们的 认为尿路上皮在保护肾脏免受梗阻性肾病中起重要作用的假说。这个 这个应用程序的目标有三个。首先，我们的目标是定义尿路上皮损伤作为驱动因素的作用。 梗阻性肾病。第二，我们将检验药物增强剂Uroplakin+细胞 尿路蛋白的生成和表达可在治疗上用于限制梗阻性肾病。最后的, 我们将测试尿路上皮蛋白作为梗阻性肾病诊断生物标志物的潜力。 接受先天性输尿管梗阻评估的儿童。这项计划的长远目标是改善 通过确定新的诊断、预后和治疗方法来预防UTO患者的护理 进行性慢性肾脏疾病。

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.