钠和尿素是建立肾皮质至髓质渗透压梯度的两大介质，其在尿浓缩机制中发挥重要作用。但目前只有针对排钠的利尿药，尚无针对排尿素的利尿药。前期发现尿素通道敲除可导致尿素选择性利尿，且不引起机体电解质平衡紊乱。因此，我们提出“尿素通道蛋白可作为利尿药作用靶点，其抑制剂可研发成新型利尿药”的科学假说，其优势在于“利尿作用不影响机体电解质平衡”。本项目拟在发现尿素通道抑制剂具有尿素选择性利尿作用，并不引起血钠、钾、氯水平改变的基础上，应用基因敲除动物模型、蛋白质结构分析、基因定点突变、蛋白质细胞内转位分析、蛋白质修饰、活性化合物筛选和药理学评价等技术，研究尿素通道UT-A1调控机制，发现UT-A1高度特异性抑制剂。本研究的目标是以UT-A1作为新型利尿药作用靶点，获得药理学特性优良的新型利尿药先导化合物。该类利尿药将给以水潴留为主的病变，如肝硬化腹水、肾病综合症、心衰等引起的顽固性水肿患者提供精准治疗。

Sodium and urea are the two major solutes that set up the kidney medullary osmolarity gradient. A number of diuretics that affect sodium excretion have been developed and used clinically. Surprisingly, there is presently no drug that affects urea excretion. Urea transport across the cell membrane is mediated by urea transporter proteins. Urea transporter UT-A1 in the kidney inner medullary collecting duct is critical for concentrating urine. Previous work showed that urea transporter knockout mice have impaired urinary concentrating ability. Interestingly, the serum electrolytes were not changed. Therefore, we propose that urea transporters may act as a new diuretic drug target. The new diuretics targeting urea transporter UT-A1 would be very promising and have two significant advantages over conventional diuretics: I) more efficacious, since UT-A1 is located in the terminal IMCD; there could be no compensation after urea reabsorption; II) fewer side effects, since UT-A1 urea transport activity does not involve Na+, K+, Ca2+, Cl- and H+, so the chance to affect electrolyte homeostasis is small. The aim of this proposal is to elucidate the molecular mechanism of UT-A1 as a new diuretic target using gene knockout, protein structure determination, site-directed mutagenesis, intracellular trafficing analysis, active compound discovery and pharmacology. The new diuretics will provide precision therapeutic interventions for diseases with total body fluid overload such as hypertension, congestive heart failure, cirrhosis, and nephrotic syndrome.