Klein Janet D, Sands Jeff M
Renal Division, Department of Medicine, and Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA.
Curr Opin Nephrol Hypertens. 2016 Sep;25(5):444-51. doi: 10.1097/MNH.0000000000000252.
Urea is transported by urea transporter proteins in kidney, erythrocytes, and other tissues. Mice in which different urea transporters have been knocked out have urine-concentrating defects, which has led to the development and testing of urea transporters Slc14A2 (UT-A) and Slc14A1 (UT-B) inhibitors as urearetics. This review summarizes the knowledge gained during the past year on urea transporter regulation and investigations into the clinical potential of urearetics.
UT-A1 undergoes several posttranslational modifications that increase its function by increasing UT-A1 accumulation in the apical plasma membrane. UT-A1 is phosphorylated by protein kinase A, exchange protein activated by cyclic AMP, protein kinase Cα, and AMP-activated protein kinase, all at different serine residues. UT-A1 is also regulated by 14-3-3, which contributes to UT-A1 removal from the membrane. UT-A1 is glycosylated with various glycan moieties in animal models of diabetes mellitus. Transgenic expression of UT-A1 into UT-A1/UT-A3 knockout mice restores urine-concentrating ability. UT-B is present in descending vasa recta and urinary bladder, and is linked to bladder cancer. Inhibitors of UT-A and UT-B have been developed that result in diuresis with fewer abnormalities in serum electrolytes than conventional diuretics.
Urea transporters play critical roles in the urine-concentrating mechanism. Urea transport inhibitors are a promising new class of diuretic agent.
尿素通过尿素转运蛋白在肾脏、红细胞及其他组织中进行转运。敲除不同尿素转运蛋白的小鼠存在尿液浓缩缺陷，这促使了尿素转运蛋白Slc14A2（UT-A）和Slc14A1（UT-B）抑制剂作为尿素利尿剂的研发与测试。本综述总结了过去一年中关于尿素转运蛋白调节的知识以及对尿素利尿剂临床潜力的研究。
UT-A1经历多种翻译后修饰，通过增加其在顶端质膜中的积累来增强其功能。UT-A1可被蛋白激酶A、环磷酸腺苷激活的交换蛋白、蛋白激酶Cα和AMP激活的蛋白激酶磷酸化，且磷酸化位点均为不同的丝氨酸残基。UT-A1还受14-3-3调节，14-3-3有助于将UT-A1从膜上移除。在糖尿病动物模型中，UT-A1会被多种聚糖部分糖基化。将UT-A1转基因表达至UT-A1/UT-A3基因敲除小鼠中可恢复其尿液浓缩能力。UT-B存在于直小血管降支和膀胱中，且与膀胱癌有关。已研发出UT-A和UT-B的抑制剂，与传统利尿剂相比，这些抑制剂导致利尿作用的同时血清电解质异常较少。
尿素转运蛋白在尿液浓缩机制中起关键作用。尿素转运抑制剂是一类有前景的新型利尿剂。
